MRCP Revision Notes: Essential Study Guide for Physicians

Essential Revision Notes for MRCP Fourth Edition Dedication To my wife, Marian, and children, Michael, Gabriella and Alicia, who will always inspire Essential Revision Notes for MRCP Fourth Edition edited by Philip A Kalra MA MB BChir FRCP MD Consultant and Honorary Professor of Nephrology, Salford Royal NHS Foundation Trust and The University of Manchester © PASTEST LTD 1999, 2004, 2009, 2014 Egerton Court Parkgate Estate Knutsford Cheshire WA16 8DX Telephone: 01565 755226 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior permissions of the copyright owner. First published 1999 Reprinted 1999 Revised edition 2002 Reprinted 2003 Second edition 2004 Third edition 2009 Reprinted 2009 Fourth edition 2014 ISBN: 1 905 635 92 4 978 1 905635 92 4 ePub ISBN: 978 1 909491 97 7 Mobi ISBN: 978 1 909491 96 0 A catalogue record for this book is available from the British Library. The information contained within this book was obtained by the authors from reliable sources. However, whilst every effort has been made to ensure its accuracy, no responsibility for loss, damage or injury occasioned to any person acting or refraining from action as a result of information contained herein can be accepted by the publishers or authors. PasTest Revision Books and Intensive Courses PasTest has been established in the field of postgraduate medical education since 1972, providing revision books and intensive study courses for doctors preparing for their professional examinations. Books and courses are available for the following specialties: MRCP Parts 1 and 2, MRCPCH Parts 1 and 2, MRCS, MRCOG Parts 1 and 2, DRCOG, DCH, FRCA, MRCGP, Dentistry. For further details contact: PasTest, Freepost, Knutsford, Cheshire WA16 7BR Tel: 01565 752000 www.pastest.co.uk Original design and typesetting by EDITEXT, Derbyshire (01457 857622). Fourth edition text prepared by Keytec Typesetting Ltd, Bridport, Dorset Printed and bound in the UK by Page Bros (Norwich) Ltd. Fax: 01565 650264 enquiries@pastest.co.uk Contents Contributors to Fourth Edition Contributors to Third Edition Permissions Preface to the Fourth Edition CHAPTER 1. Cardiology J E R Davies, S Nijjer 2. Clinical Pharmacology, Toxicology and Poisoning S Waring 3. Dermatology H Robertshaw 4. Endocrinology T Kearney, S Giritharan, M Kumar 5. Epidemiology J Ritchie 6. Gastroenterology S Lal, D H Vasant 7. Genetics E Burkitt Wright 8. Genito-urinary Medicine and AIDS B Goorney 9. Haematology K Patterson 10. Immunology J Galloway Infectious Diseases and Tropical Medicine 11. C L van Halsema 12. Maternal Medicine L Byrd 13. Metabolic Diseases S Sinha 14. Molecular Medicine K Siddals 15. Nephrology P Kalra 16. Neurology M Jones, C Kobylecki, D Rog 17. Ophthalmology K Smyth 18. Psychiatry E Sampson 19. Respiratory Medicine H Green 20. Rheumatology M McMahon 21. Statistics E Koutoumanou Index Contributors to Fourth Edition Emma Burkitt Wright MBChB PhD MRCP(UK) Specialist Registrar and Honorary Clinical Research Fellow, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals Foundation Trust and University of Manchester, Chapter 7 Genetics Louise Byrd MBBS, MRCOG, Dip RCR/RCOG Cert. Medical Education Consultant in High Risk Obstetrics and Maternal Medicine with special interest in Medical Education, Central Manchester Foundation Trust, Manchester, Chapter 12 Maternal Medicine Justin E R Davies BSc, MBBS, PhD, MRCP Senior Research Fellow and Consultant Cardiologist, Imperial College London, Chapter 1 Cardiology James Galloway MBChB, MRCP, MSc, PhD, CHP Clinical Lecturer / Honorary Consultant Rheumatologist, Department of Rheumatology, King’s College Hospital, London, Chapter 10 Immunology Sumithra Giritharan MBChB MRCP(UK) Specialist Registrar, Department of Diabetes and Endocrinology, Salford Royal NHS Foundation Trust, Manchester, Chapter 4 Endocrinology Ben Goorney MBChB FRCP Consultant Genito-Urinary Physician, Department of Genito-Urinary Medicine, Hope Hospital, Salford, Chapter 8 Genito-Urinary Medicine and AIDS Heather Green BSc, MBChB (Hons), MRCP(UK), Certificate in Respiratory Medicine Respiratory Registrar/Research Fellow in Cystic Fibrosis, Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester, Manchester, Chapter 19 Respiratory Medicine Matthew Jones MD MRCP Consultant Neurologist and Clinical Teaching Fellow, Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Salford, Chapter 16 Neurology Philip A Kalra MA MB BChir FRCP MD Consultant and Honorary Professor of Nephrology, Salford Royal NHS Foundation Trust and University of Manchester, Chapter 15 Nephrology Eirini Koutoumanou BSc MSc Senior Teaching Fellow, UCL Institute of Child Health, Population, Policy, Practice Programme, London, Chapter 21 Statistics Tara Kearney MB BS, BSc(Hons), FRCP, MD Consultant Endocrinologist, Salford Royal Foundation NHS Trust, Manchester, Chapter 4 Endocrinology Mohit Kumar MBChB MRCP Specialist Trainee, Department of Diabetes, Endocrinology and Weight Management, Salford Royal Foundation Trust, Salford Manchester, Chapter 4 Endocrinology Simon Lal BSc MBChB PhD FRCP Consultant Gastroenterologist, Salford Royal NHS Foundation Trust, Salford, Chapter 6 Gastroenterology Michael McMahon BSc MBChB FRCP Consultant Physician and Rheumatologist, Department of Rheumatology, Dumfries and Galloway Royal Infirmary, Dumfries, Chapter 20 Rheumatology Sukhjinder S Nijjer BSc (Hons) MBChB (Hons) MRCP(UK) Cardiology Registrar, Hammersmith Hospital and the International Centre for Circulatory Health, Imperial College London, Chapter 1 Cardiology Keith Patterson FRCP FRCPath Consultant Haematologist, London, Chapter 9 Haematology James Ritchie MBChB, MRCP PhD Clinical Research Fellow, Department of Renal Medicine, Salford Royal Hospital, Salford, Manchester, Chapter 5 Epidemiology Helen Robertshaw BSc(Hons) MBBS FRCP Consultant in Dermatology, Royal Bournemouth and Christchurch Hospitals, Bournemouth, Chapter 3 Dermatology David Rog BMedSci (Hons), BMBS, FRCP, MD Consultant Neurologist and Honorary Lecturer, Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal NHS Foundation Trust, Salford, Chapter 16 Neurology Liz Sampson MBChB MRCPsych MD MSc Clinical Senior Lecturer In Old Age Psychiatry, Division of Psychiatry, University College London. Consultant in Liaison Psychiatry, Barnet Enfield and Haringey Mental Health Trust London, Chapter 18 Psychiatry Kirk W Siddals BSc PhD Research Fellow, Vascular Research, Salford Royal Hospital, Manchester, Chapter 14 Molecular Medicine Smeeta Sinha MBChB PhD MRCP FRCP Consultant and Honorary Senior Lecturer in Nephrology, Salford Royal NHS Foundation Trust, Salford, Chapter 13 Metabolic Diseases Katherine Smyth MBChB MRCP FRCOpth Consultant Ophthalmologist, Royal Bolton Hospital, Bolton, Chapter 17 Ophthalmology Clare L van Halsema MBChB MSc MD MRCP DTM&H Dip HIV Med Specialist Registrar in Infectious Diseases, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Manchester, Chapter 11 Infectious Diseases and Tropical Medicine Dipesh H Vasant MB ChB, MRCP(UK) Clinical Research Fellow and Specialist Registrar in Gastroenterology and Medicine, The University of Manchester Clinical Sciences Building, Salford Royal NHS Trust, Chapter 6 Gastroenterology Stephen Waring PhD FRCP (Edin) FRCP FBPharmacolS Consultant in Acute Medicine & Toxicology, Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, York, Chapter 2 Clinical Pharmacology, Toxicology and Poisoning Contributors to Third Edition Emma Burkitt Wright MBCh MPhil MRCP(UK) Academic Clinical Fellow, Medical Genetics Research Group and University of Manchester, St Mary’s Hospital, Manchester Genetics Louise Byrd MRCOG Specialist Registrar in Obstetrics and Gynaecology, North West Region Maternal Medicine Colin M Dayan MA MBBS FRCP PhD Consultant Senior Lecturer in Medicine, Head of Clinical Research, URCN, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol Endocrinology Ben Goorney MBChB FRCP Consultant Genito-Urinary Physician, Department of Genito-Urinary Medicine, Hope Hospital, Salford Genito-urinary Medicine and AIDS Philip A Kalra MA MB BChir FRCP MD Consultant Nephrologist and Honorary Reader, Hope Hospital, Salford Nephrology Mike McMahon BSc MBChB FRCP Consultant Physician and Rheumatologist, Department of Rheumatology, Dumfries and Galloway Royal Infirmary, Dumfries Immunology & Rheumatology John Paisey DM MRCP Consultant Cardiac Electrophysiologist, Royal Bournemouth Hospital, Bournemouth Cardiology Keith Patterson FRCP FRCPath Consultant Haematologist, Department of Haematology, University College London Hospitals, London Haematology Jaypal Ramesh MRCP(UK) Consultant Gastroenterologist, University Hospital of South Manchester, NHS Foundation Trust, Manchester Gastroenterology Geraint Rees BA BMBCh MRCP PhD Wellcome Senior Clinical Fellow, Institute of Cognitive Neuroscience, University College London Neurology Helen Robertshaw BSc(Hons) MBBS MRCP Specialist Registrar in Dermatology, Southampton University Hospitals Trust, Southampton Dermatology Liz Sampson MBChB MRCPsych MD Lecturer in Old Age Psychiatry, Royal Free and University College Medical School, University College London Psychiatry Kirk W Siddals BSc PhD Research Fellow, Vascular Research, Salford Royal Hospital, Stott Lane, Salford Molecular Medicine Smeeta Sinha MBChB MRCP Specialist Registrar Nephrology, Salford Royal NHS Foundation Trust, Salford, Manchester Metabolic Diseases Katherine Smyth MBChB MRCP FRCOpth Consultant Opthalmologist, Royal Bolton Hosptial, Bolton Ophthalmology Clare L van Halsema MBChB MRCP DTM&H Specialist Registrar in Infectious Diseases, Monsall Unit, Department of Infectious Diseases and Tropical Medicine, North Manchester General Hospital, Manchester Infectious Diseases Angie Wade MSc PhD CStat ILTM Senior Lecturer in Medical Statistics, Institute of Child Health and Great Ormond Street Hospital, London Statistics Deborah A Wales MBChB MRCP FRCA Consultant Respiratory Physician, Nevill Hall Hospital, Brecon Road, Abergavenny, Monmouthshire Respiratory Medicine GaryWhitlock BHB MBChB MPH(Hons) PhDFAFPHM Clinical Research Fellow, Clinical Trial Service Unit, University of Oxford Epidemiology Stephen Waring MRCP(UK) Consultant Physician in Acute Medicine and Toxicology, The Royal Infirmary of Edinburgh Clinical Pharmacology Permissions The following have been reproduced with kind permission from BMJ Publishing Group Ltd. Cardiology Fig 1.5 – Radionuclide myocardial perfusion imaging. Left panel shows the gamma camera. Right panel shows a reversible inferolateral perfusion defect: left column stress, right column rest. Fig 1.6 – Mechanism for atrioventricular nodal re-entry tachycardia Fig 1.7 – Mechanism for atrioventricular re-entry tachycardia Maternal Medicine Table 12.4 – Specific renal diseases and pregnancy Neurology Figure 16.2 – Demonstrating how the ‘shape’ of three common neurological conditions – seizures, transient ischaemic attacks and migraine – and their positive and negative neurological features in the history help to differentiate them. The following images in this book have been reproduced with kind permission from Science Photo Library. Immunology Fig 10.3 – Angioedema on the tongue Preface to the Fourth Edition I am delighted that ‘Essential Revision Notes for MRCP’ has retained it’s place as one of the key texts for preparation for the MRCP over a period now extending beyond 15 years. In this latest edition there has been a significant revision of the text in all of the chapters by experts in the subject, and the material has been brought right up to date with coverage of the latest clinical developments in the subject areas. We continue to use the same successful style of layout within the Essential Revision Notes (ERN) with emphasis upon ‘user-friendliness’ with succinct text, bullet points and tables. The doublecolumn format enhances readability and revision. The aim is to provide the practising physician with accessible, concise and up-to-date core knowledge across all of the subspecialties of medicine. For candidates who are preparing for the MRCP, it fills a unique gap between large detailed textbooks of medicine and those smaller texts which concentrate specifically on how to pass the examinations. However, many physicians use the ERN as a career-long companion to be used as a concise source of reference long after they have successfully collected their exam certificates. A special thanks goes to our skilled team of contributing authors for their outstanding efforts which have ensured that this new edition maintains the standard set by previous editions. I am also particularly grateful to Cathy Dickens, who has been a key contributor to the ERN effort since it’s initiation in 1998, and to Brad Fallon, for co-ordinating the book production process at PasTest. Philip A Kalra Consultant and Honorary Professor of Nephrology Salford Royal NHS Foundation Trust and University of Manchester Chapter 1 Cardiology CONTENTS 1.1 Introduction 1.2 Clinical examination 1.2.1 Jugular venous pressure 1.2.2 Arterial pulse associations 1.2.3 Cardiac apex 1.2.4 Heart sounds 1.3 Cardiac investigations 1.3.1 Electrocardiography 1.3.2 Echocardiography 1.3.3 Nuclear cardiology: myocardial perfusion imaging 1.3.4 Cardiac catheterisation 1.3.5 Exercise stress testing 1.3.6 24-hour ambulatory blood pressure monitoring 1.3.7 Computed tomography 1.3.8 Magnetic resonance imaging 1.4 Valvular disease and endocarditis 1.4.1 Murmurs 1.4.2 Mitral stenosis 1.4.3 Mitral regurgitation 1.4.4 Aortic regurgitation 1.4.5 Aortic stenosis 1.4.6 Tricuspid regurgitation 1.4.7 Prosthetic valves 1.4.8 Infective endocarditis 1.5 Congenital heart disease 1.5.1 Atrial septal defect 1.5.2 Ventricular septal defect 1.5.3 1.5.4 1.5.5 1.5.6 1.5.7 Patent ductus arteriosus Coarctation of the aorta Eisenmenger syndrome Tetralogy of Fallot Important post-surgical circulations 1.6 Arrhythmias and pacing 1.6.1 Bradyarrhythmias 1.6.2 Supraventricular tachycardias 1.6.3 Atrial arrhythmias 1.6.4 Ventricular arrhythmias and channelopathies 1.6.5 Pacing and ablation procedures 1.7 Ischaemic heart disease 1.7.1 Angina 1.7.2 Myocardial infarction 1.7.3 PPCI for STEMI 1.7.4 Coronary artery interventional procedures 1.8 Heart failure and myocardial diseases 1.8.1 Cardiac failure 1.8.2 Hypertrophic cardiomyopathy 1.8.3 Dilated cardiomyopathy 1.8.4 Restrictive cardiomyopathy 1.8.5 Myocarditis 1.8.6 Cardiac tumours 1.8.7 Alcohol and the heart 1.8.8 Cardiac transplantation 1.9 Pericardial disease 1.9.1 Constrictive pericarditis 1.9.2 Pericardial effusion 1.9.3 Cardiac tamponade 1.10 Disorders of major vessels 1.10.1 Pulmonary hypertension 1.10.2 Venous thrombosis and pulmonary embolism 1.10.3 Systemic hypertension 1.10.4 Aortic dissection Appendix I Normal cardiac physiological values Appendix II Summary of further trials in cardiology Cardiology 1.1 INTRODUCTION Patients with cardiovascular disease form a large part of clinical work and accordingly have prominence in the MRCP examination. Ischaemic heart disease, valvular disease and arrhythmic disorders have the largest preponderance of questions. Many of the conditions have overlapping causes and cardiac pathophysiology is such that one condition can lead to another. Understanding the pathophysiology will allow clinicians to unpick diagnoses, understand the diseases and answer examination questions more effectively. 1.2 CLINICAL EXAMINATION 1.2.1 Jugular venous pressure This is an essential clinical sign that reflects patient filling status and is essential to detect for correct fluid management. The jugular venous pressure (JVP) reflects right atrial pressure, and in healthy individuals at 45° is 3 cm in vertical height above the sternal angle (the angle of Louis, the manubriosternal junction). Inspiration generates negative intrathoracic pressure and a suction of venous blood towards the heart, causing the JVP to fall (Figure 1.1). Figure 1.1 The location and wave-form of the jugular venous pressure (JVP). The JVP must be assessed with the patient at 45° Normal waves in the JVP The a wave Due to atrial contraction – actively push up superior vena cava (SVC) and into the right ventricle (may cause an audible S4). The c wave An invisible flicker in the x descent due to closure of the tricuspid valve, before the start of ventricular systole. The x descent Downward movement of the heart causes atrial stretch and a drop in pressure. The v wave Due to passive filling of blood into the atrium against a closed tricuspid valve. The y descent Opening of the tricuspid valve with passive movement of blood from the right atrium to the right ventricle (causing an S3 when audible). Causes of a raised JVP 1. Raised JVP with normal waveform: • Heart failure – biventricular or isolated right heart failure • Fluid overload of any cause • Severe bradycardia. Raised JVP upon inspiration and drops with expiration: Kussmaul’s sign is the opposite of what occurs in health and implies that the right heart chambers cannot increase in size to 2. 3. accommodate increased venous return. This can be due to pericardial disease (constriction) or fluid in the pericardial space (pericardial effusion and cardiac tamponade). Raised JVP with loss of normal pulsations: SVC syndrome is obstruction caused by mediastinal malignancy, such as bronchogenic malignancy, which causes head, neck and/or arm swelling. Pathological waves in the JVP This is a common source of MRCP Part 1 questions. See Table 1.1 and Figure 1.2 for these waves. Table 1.1 Pathological waves in the jugular venous pressure (JVP) a Absent Atrial fibrillation – no co-ordinated contraction waves Large Tricuspid stenosis, right heart failure, pulmonary hypertension Caused by atrioventricular dissociation – allowing the atria and ventricles to Cannon contract at same time: Atrial flutter and atrial tachycardias Third-degree (‘complete’) heart block Ventricular tachycardia and ventricular ectopics v Giant waves Tricuspid regurgitation – technically a giant ‘c-V’ wave x Steep descent Tamponade and cardiac constriction If steep x descent only, then tamponade y Steep descent Slow Cardiac constriction Tricuspid stenosis Figure 1.2 Different JVP morphologies can reflect different disease states 1.2.2 Arterial pulse associations The radial arterial pulse is suitable for assessing the rate and rhythm, and whether it is collapsing. The central arterial pulses, preferably the carotid, are used to assess the character. Absent radial pulse • • • • • • Iatrogenic: post-catheterisation or arterial line Blalock–Taussig shunt for congenital heart disease, eg tetralogy of Fallot Aortic dissection with subclavian involvement Trauma Takayasu’s arteritis Peripheral arterial embolus. Pathological pulse characters • • • • • Collapsing: aortic regurgitation, arteriovenous fistula, patent ductus arteriosus (PDA) or other large extracardiac shunt Slow rising: aortic stenosis (delayed percussion wave) Bisferiens: a double shudder due to mixed aortic valve disease with significant regurgitation (tidal wave second impulse) Jerky: hypertrophic obstructive cardiomyopathy Alternans: occurs in severe left ventricular dysfunction. The ejection fraction is reduced meaning the end-diastolic volume is elevated. This may sufficiently stretch the myocytes (Frank–Starling physiology) to improve the the ejection fraction of the next heart beat. This leads to pulses that alternate from weak to strong Paradoxical (pulsus paradoxus): an excessive reduction in the pulse with inspiration (drop in • systolic BP >10 mmHg) occurs with left ventricular compression, tamponade, constrictive pericarditis or severe asthma as venous return is compromised. 1.2.3 Cardiac apex The cardiac apex pulsation reflects the ventricle striking the chest wall during isovolumetric contractions, and gives an indication of the position of the left ventricle and it size. It is typically palpable in the fifth intercostal space in the midclavicular line. Absent apical impulse • • • • Obesity/emphysema Right pneumonectomy with displacement Pericardial effusion or constriction Dextrocardia (palpable on right side of chest) Pathological apical impulse • • • • • • • • Heaving: left ventricular hypertrophy (LVH) (and all its causes), sometimes associated with palpable fourth heart sound Thrusting/hyperdynamic: high left ventricular volume (eg in mitral regurgitation, aortic regurgitation, PDA, ventricular septal defect) Tapping: palpable first heart sound in mitral stenosis Displaced and diffuse/dyskinetic: left ventricular impairment and dilatation (eg dilated cardiomyopathy, myocardial infarction [MI]) Double impulse: with dyskinesia is due to left ventricular aneurysm; without dyskinesia in hypertrophic cardiomyopathy (HCM) Pericardial knock: constrictive pericarditis Parasternal heave: due to right ventricular hypertrophy (eg atrial septal defect [ASD], pulmonary hypertension, chronic obstructive pulmonary disease [COPD], pulmonary stenosis) Palpable third heart sound: due to heart failure and severe mitral regurgitation. 1.2.4 Heart sounds Abnormalities of first heart sounds are given in Table 1.2 and of second heart sounds in Table 1.3. Third heart sound (S3) Due to the passive filling of the ventricles on opening of the atrioventricular (AV) valves, audible in normal children and young adults. Pathological in cases of rapid left ventricular filling (eg mitral regurgitation, ventricular septal defect [VSD], congestive cardiac failure and constrictive pericarditis). Table 1.2 Abnormalities of the first heart sound (S1): closure of mitral and tricuspid valves Loud Soft Split Mobile mitral stenosis Immobile mitral stenosis RBBB Hyperdynamic states Hypodynamic states LBBB Mitral regurgitation Poor ventricular Left-to-right shunts function Short PR interval Long PR interval Tachycardic states Vari able Atrial fibrilla tion Compl ete heart block VT Inspiration Ebstein’s anomaly LBBB, left bundle-branch block; RBBB, right bundle-branch block; VT, ventricular tachycardia. Table 1.3 Abnormalities of the second heart sound (S2): closure of aortic then pulmonary valves (<0.05 s apart) Intensity Loud: Systemic hypertension (loud A2) Pulmonary hypertension (loud P2) Tachycardic states ASD (loud P2) Soft or absent: Severe aortic stenosis Splitting Fixed: ASD Widely split: RBBB Pulmonary stenosis Deep inspiration Mitral regurgitation Single S2: Severe pulmonary stenosis/aortic stenosis Hypertension Large VSD Tetralogy of Fallot Eisenmenger’s syndrome Pulmonary atresia Elderly Reversed split S2: LBBB Right ventricular pacing PDA Aortic stenosis A2, aortic second sound; ASD, atrial septal defect; LBBB, left bundle-branch block; P2, pulmonary second sound; PDA, patent ductus arteriosus; RBBB, right bundle-branch block; VSD, ventricular septal defect. Fourth heart sound (S4) Due to the atrial contraction that fills a stiff left ventricle, such as in LVH, amyloid, HCM and left ventricular ischaemia. It is absent in atrial fibrillation. Causes of valvular clicks • • • Aortic ejection: aortic stenosis, bicuspid aortic valve Pulmonary ejection: pulmonary stenosis Mid-systolic: mitral valve prolapse. Opening snap In mitral stenosis an opening snap (OS) can be present and occurs after S2 in early diastole. The closer it is to S2 the greater the severity of mitral stenosis. It is absent when the mitral cusps become immobile due to calcification, as in very severe mitral stenosis. 1.3 CARDIAC INVESTIGATIONS 1.3.1 Electrocardiography Both the axis and sizes of QRS vectors give important information. Axes are defined as: • • • • −30° to +90°: normal −30° to −90°: left axis +90° to +180°: right axis −90° to −180°: indeterminate. Tip: if the QRS is positive in leads 1 and aVF the axis is normal. The causes of common abnormalities are given in the box below. Electrocardiography (ECG) strips illustrating typical changes in common disease states are shown in Figure 1.3. Causes of common abnormalities in the ECG • • Causes of left axis deviation • Left bundle-branch block (LBBB) • Left anterior hemi-block (LAHB) • LVH • Primum ASD • Cardiomyopathies • Tricuspid atresia Low-voltage ECG • Pulmonary emphysema • Pericardial effusion • Myxoedema • Severe obesity • Incorrect calibration • Cardiomyopathies • Global ischaemia • Amyloid Causes of right axis deviation • Infancy • Right bundle-branch block (RBBB) Right ventricular hypertrophy (eg lung disease, pulmonary embolism, large secundum ASD, • severe pulmonary stenosis, tetralogy of Fallot) Abnormalities of ECGs in athletes • Sinus arrhythmia • Sinus bradycardia • First-degree heart block • Wenckebach’s phenomenon • Junctional rhythm • • Clinical diagnoses that can be made from the ECG of an asymptomatic patient • • • • • • • Atrial fibrillation Complete heart block HCM ASDs (with RBBB) Long QT and Brugada’s syndromes Wolff–Parkinson–White (WPW) syndrome (δ waves) Arrhythmogenic right ventricular dysplasia (cardiomyopathy). Short PR interval This is rarely <0.12 s; the most common causes are those of pre-excitation involving accessory pathways or of tracts bypassing the slow region of the AV node; there are other causes. • • Pre-excitation • WPW syndrome • Lown–Ganong–Levine syndrome (short PR syndrome) Other • Ventricular extrasystole falling after P wave • AV junctional rhythm (but P wave will usually be negative) • Low atrial rhythm • Coronary sinus escape rhythm • Normal variant (especially in young people) Causes of tall R waves inV1 It is easy to spot tall R waves in V1. This lead largely faces the posterior wall of the left ventricle and the mass of the right ventricle. As the overall vector is predominantly towards the bulkier left ventricle in normal situations, the QRS is usually negative in V1. This balance can be reversed in the following situations: Figure 1.3 ECG strips demonstrating typical changes in common disease states • • • • • • Right ventricular hypertrophy (myriad causes) RBBB Posterior infarction Dextrocardia WPW syndrome with left ventricular pathway insertion (often referred to as type A) HCM (septal mass greater than posterior wall). Posterior infarctions are easily missed because the rest of the ECG can be normal. Recognition of positive tall R waves in V1 can be the only sign with a typical history; there may be subtle ST depression in V1–V3. Performing a posterior ECG with leads placed over the back will reveal ST elevation. Bundle-branch block and ST-segment abnormalities Complete bundle-branch block is a failure or delay of impulse conduction to one ventricle from the AV node, requiring conduction via the other bundle, and then transmission within the ventricular myocardium; this results in abnormal prolongation of QRS duration (>120 ms) and abnormalities of the normally isoelectric ST segment. In contrast to RBBB, LBBB is always pathological. During the hyperacute and acute phases of cerebral events, including ischaemic stroke and haemorrhage, marked ST changes may be observed on the ECG and there may even be an associated rise in cardiac troponin. These changes result from abnormal autonomic discharges due to intense sympathetic nervous activation, with consequent myocytolysis, which accounts for troponin leak. • • • • Causes of LBBB • Ischaemic heart disease (recent or old MI) • Hypertension • LVH • Aortic valve disease • Cardiomyopathy • Myocarditis • Post-valve replacement • Right ventricular pacemaker • Tachycardia with aberrancy or concealed conduction • Ventricular ectopy Causes of RBBB • Normal in young people • Right ventricular strain (eg pulmonary embolus) • ASD • Ischaemic heart disease • Myocarditis • Idiopathic • Tachycardia with aberrancy or concealed conduction • Ventricular ectopy Causes of ST elevation • Early repolarisation • Acute MI • Pericarditis (saddle shaped) • Ventricular aneurysm • Coronary artery spasm • During angioplasty • Non-standard ECG acquisition settings (eg on monitor) Other ST–T wave changes (not elevation) • • • • • • • • • • Ischaemia: Digoxin therapy: Hypertrophy: Post-tachycardia: Hyperventilation: Oesophageal/upper abdominal irritation: Cardiac contusion: Mitral valve prolapse: Acute cerebral event (eg subarachnoid haemorrhage): Electrolyte abnormalities ST depression, T inversion and peaking downsloping ST depression ST depression, T inversion ST depression, T inversion ST depression, T inversion and peaking ST depression, T inversion ST depression, T inversion T-wave inversion ST depression, T inversion Q waves can be permanent (reflecting myocardial necrosis) or transient (suggesting failure of myocardial function, but not necrosis). • • Permanent Q waves • Transmural infarction • LBBB • WPW syndrome • HCM • Idiopathic cardiomyopathy • Amyloid heart disease • Neoplastic infiltration • Friedreich’s ataxia • Dextrocardia • Sarcoidosis • Progressive muscular dystrophy • Myocarditis (may resolve) Transient Q waves • Coronary spasm • Hypoxia • Hyperkalaemia • Cardiac contusion • Hypothermia Potassium and ECG changes There is a reasonable correlation between plasma potassium and ECG changes. • • • Hyperkalaemia • Tall T waves • Prolonged PR interval • Flattened/absent P waves Very severe hyperkalaemia • Wide QRS • Sine wave pattern • Ventricular tachycardia/ventricular fibrillation/asystole Hypokalaemia • Flat T waves, occasionally inverted • Prolonged PR interval • ST depression • Tall U waves ECG changes after coronary artery bypass surgery • • • • • • • • • U waves (hypothermia) Saddle-shaped ST elevation (pericarditis) PR-segment depression (pericarditis) Low-voltage ECG in chest leads (pericardial effusion) Changing electrical alternans (alternating ECG axis – cardiac tamponade) S1Q3T3 (pulmonary embolus) Atrial fibrillation Q waves ST-segment and T-wave changes. ECG techniques for prolonged monitoring • • • • Holter monitoring: the ECG is monitored in one or more leads for 24–72 h. The patient is encouraged to keep a diary in order to correlate symptoms with ECG changes External recorders: the patient keeps a monitor with them for a period of days or weeks. At the onset of symptoms the monitor is placed to the chest and this records the ECG Wearable loop recorders: the patient wears a monitor for several days or weeks. The device records the ECG constantly on a self-erasing loop. At the time of symptoms, the patient activates the recorder and a trace spanning some several seconds before a period of symptoms to several minutes afterwards is stored Implantable loop recorders: a loop recorder is implanted subcutaneously in the pre-pectoral region. The recorder is activated by the patient or according to pre-programmed parameters. Again the ECG data from several seconds before symptoms to several minutes after are stored; data are uploaded by telemetry. The battery life of the implantable loop recorder varies between 18–36 months. 1.3.2 Echocardiography Principles of the technique Sound waves emitted by a transducer are reflected back differentially by tissues of variable acoustic properties. Moving structures (including fluid structures) reflect sound back as a function of their own velocity. The signal-to-noise ratio is improved by minimising the distance and number of acoustic structures between the transducer and the object being recorded. M-mode: named after appearance of the mitral valve on this modality, this is a longitudinal beam that achieves high temporal resolution for a given location. It allows calculations of left atrial (LA) size, aortic root, left ventricular (LV) outflow tract (LVOT), and ventricular end-systolic and end-diastolic dimensions. These are typically made in the parasternal long-axis view. Doppler measurements: the Doppler phenomenon is used to measure the velocity of blood flow for estimation of pressure gradients across valve abnormalities. Velocities can be measured along the length of the Doppler beam (continuous-wave Doppler, useful for aortic stenosis assessment), or at a specific location (pulsed-wave Doppler, useful for LV filling patterns or for measuring the velocity of myocardial tissue movement). Two-dimensional echocardiography: the piezoelectric crystals in the probe head are activated in sequence to reconstruct a two-dimensional image of the heart. This allows identification of anatomy and structural abnormalities, eg enlarged structures, abnormal valves or abnormal communications between chambers. Newer probes can produce three-dimensional images to better visualise defects. Colour Doppler: this applies Doppler to assess the average velocities of blood within a region of interest. Movement of blood can be coded red (moving towards transducer) or blue (moving away from transducer) known as the BART convention (blue = away red = toward). This helps identify and quantify valvular regurgitation. Diagnostic uses of echocardiography Conventional echocardiography is used in the diagnosis of: • • • • • • Pericardial effusion and tamponade Valvular disease (including large vegetations) HCM, dilated cardiomyopathy, LV mass and function Cardiac tumours and intracardiac thrombus Congenital heart disease (eg PDA, coarctation of the aorta) Right ventricular function and pressure. Stress echo is used in the diagnosis of myocardial viability and ischaemia, to help risk stratify patients and consider them for further investigations such as coronary angiography. Resting images are acquired and then stress is induced, by either intravenous dobutamine infusion or exercise performed on a bike or treadmill. Stress images are then acquired in the long-axis and short-axis views at moderate and peak heart rates and compared with resting images, typically arranged in a grid for ease of comparison. Contrast may be required for optimal myocardial definition – it appears bright. Regional wall motion abnormalities such as hypokinesia, dyskinesia and akinesia are defined in a 16- or 17-segment model of the left ventricle. Patients should avoid β blockers before stress echocardiography, because these will attenuate peak heart rate response. Standard contrast echo is used in the diagnosis of right-to-left shunts, particularly for patent foramen ovale (PFO) but also ASD and ventricular septal defect (VSD). Agitated saline or Gelofusine is injected into the venous system and the patient is asked to undergo Valsalva’s manoeuvre to encourage increased right-sided pressure. Bubbles may then be observed crossing from the right atrium to the left ventricle through a PFO or ASD. Transpulmonary contrast echo is used to improve discrimination between the blood pool and the endocardium to help definition in those individuals whose characteristics lead to poor image quality. It is also used to diagnose LV thrombus and other specific conditions (eg the congenital failure of muscle fibre alignment [known as non-compaction] and apical hypertrophy). Tissue Doppler imaging is a new technique that applies Doppler principles to analyse the velocity of myocardial motion. Specifically, the movement of a given cardiac wall can be interrogated by manually selecting the region of interest on the echo machine. Each wall will have a unique pattern of velocities, from which many different calculations can be made, most commonly to estimate cardiac function and pressures. Values will vary according to the site, and the age and function of the heart. Tissue Doppler differs from conventional Doppler, which focuses on the velocity of blood, and is used to assess blood flow across valves and the rate of ventricular filling. Transoesophageal echocardiography (TOE) is performed under general anaesthesia or in sedated patients with local anaesthetic applied to the oropharynx. The probe is passed into the oesophagus, meaning that it is closer to the cardiac structures, improving image quality. It is indicated in the diagnosis of aortic dissection (when a CT aortogram is delayed), suspected atrial thrombus (before cardioversion of atrial arrhythmia), assessment of vegetations or abscesses in endocarditis, prosthetic valve dysfunction or leakage, and the intraoperative assessment of LV function or success of valvular repair. It may also be indicated when transthoracic images are suboptimal. Three-dimensional echocardiography has increasing clinical application in better understanding structural anatomy. This is particularly useful for planning therapy to valvular heart disease, whether it is surgical or percutaneous replacement. Often imaging is performed during the procedure to guide valve placement. It has particular usefulness in congenital heart disease. It can be performed using either transthoracic or transoeophageal approaches. Intravascular ultrasonography (IVUS) is performed by placing a small probe mounted on a catheter on an intracoronary wire during coronary angioplasty. It provides high-resolution imaging of coronary arteries for measurement of stenosis severity and plaque characteristics, and assessment of the success of stent deployment. Intracardiac ultrasonography images the heart chambers from within; it is used mainly in those with congenital heart disease and in electrophysiological procedures. Classic M-mode patterns Due to improvements in real-time image quality. M-mode imaging is now used less in clinical practice; it does, however, allow interpretable traces to be printed as still images, and these still occasionally feature in exams. Particular M-mode patterns that have been used in past MRCP exams include: • • • • Aortic regurgitation: fluttering of the anterior mitral leaflet is seen HCM: systolic anterior motion (SAM) of the mitral valve leaflets and asymmetrical septal hypertrophy (Figure 1.4) Mitral valve prolapse: one or both leaflets prolapse during systole Mitral stenosis: the opening profile of the cusps is flat and multiple echoes are seen when there is calcification of the cusps. Figure 1.4 Classic valvular disease patterns seen with M-mode echocardiography 1.3.3 Nuclear cardiology: myocardial perfusion imaging (Figure 1.5) Perfusion tracers such as thallium or technetium can be used to gauge myocardial blood flow, both at rest and during exercise- or drug-induced stress. Tracer uptake is detected using tomograms and displayed in a colour scale in standard views. Lack of uptake may be: • Physiological: due to lung or breast tissue absorption Pathological: reflecting ischaemia, infarction or other conditions in which perfusion • abnormalities also occur (eg HCM or amyloidosis). Pathological perfusion defects are categorised as fixed (scar) and reversible (viable but ischaemic tissue). MPI can be used to: • • • • Detect infarction Investigate atypical chest pains Assess ventricular function Determine prognosis and detect myocardium that may be ‘re-awakened’ from hibernation with an improved blood supply (eg after coronary artery bypass grafting [CABG]). 1.3.4 Cardiac catheterisation Coronary and ventricular angiography Direct injection of radio-opaque contrast into the coronary arteries allows high-resolution assessment of restrictive lesions and demonstrates any anomalies. Left ventriculography provides a measure of ventricular systolic function. Angiography is typically performed via the femoral artery or radial artery through a sheath that allows insertion of specifically designed catheters that intubate the coronary vessels. Contrast can be hand injected or injected by automated pumps. Imaging is acquired by fluoroscopy. The contrast provides an image of the vessel lumen but the other parts of the vessel are poorly visualised. The lumen is carefully assessed for narrowings or stenoses, which represent coronary atherosclerotic lesions that limit blood flow. Multiple different radiographic views are required to view each vessel, because stenoses can be hidden in different projections. Figure 1.5 Radionuclide myocardial perfusion imaging. Left panel shows the gamma camera. Right panel shows a reversible inferolateral perfusion defect: left column stress, right column rest. The severity of a stenosis can be gauged visually, reported as a percentage of the vessel, or measured objectively using quantitative coronary angiography (QCA), which uses computer-aided edge detection of coronary vessels. IVUS and optical coherence tomography (OCT) are intracoronary tools used to visualise the stenosis severity and estimate the lumen area occupied by atherosclerotic plaque. Functional, or physiological, lesion severity can be detected using a wire with a tiny pressure sensor on it placed distal to a stenosis to estimate the degree of pressure drop in comparison to the aortic pressure. Percutaneous coronary intervention (PCI) can be performed immediately after coronary angiography or at a later occasion. It involves the treatment of stenoses using balloon inflation and stent deployment. Intervention is most commonly performed for the treatment of coronary obstruction in acute coronary syndrome. Other indications include primary PCI (PPCI) for acute treatment of an MI or in symptomatic stable angina where there is evidence of cardiac ischaemia. Complications of cardiac catheterisation Complications are uncommon (approximately 1%, including minor complications); these include contrast allergy, local haemorrhage from puncture sites with subsequent occurrence of thrombosis, retroperitoneal haemorrhage, false aneurysm formation (which can be compressed or injected) or arteriovenous malformation. Vasovagal reactions are common. Other complications are: • • • • • Coronary dissection: (particularly the right coronary artery in women) and aortic dissection or ventricular perforation Air or atheroma embolism: in the coronary or other arterial circulations, with consequent ischaemia or strokes Ventricular dysrhythmias: can even cause death in the setting of left main stem disease Mistaken cannulation and contrast injection into the conus branch of the right coronary artery can cause ventricular fibrillation Overall mortality rates are quoted at <1/1000 cases. 1.3.5 Exercise stress testing This is used in the investigation of coronary artery disease, exertion-induced arrhythmias, and the assessment of cardiac workload and conduction abnormalities. Exercise tests also give diagnostic and prognostic information post-infarction, and generate patient confidence in rehabilitation after an MI. Diagnostic sensitivity is improved if the test is conducted with the patient having discontinued antianginal (especially rate-limiting) medication. The main contraindications to exercise testing include those conditions where fatal ischaemia or arrhythmias may be provoked, or where exertion may severely and acutely impair cardiac function. These include the following: • • • • • • • • • Severe aortic stenosis or HCM with marked outflow obstruction Acute myocarditis or pericarditis Pyrexial or coryzal illness Severe left main stem disease Untreated congestive cardiac failure Unstable angina Dissecting aneurysm Ongoing tachy- or bradyarrhythmias Untreated severe hypertension. Indicators of a positive exercise test result The presence of each factor is additive in the overall positive prediction of coronary artery disease: • • • • • Development of anginal symptoms A fall in BP of >15 mmHg or failure to increase BP with exercise Arrhythmia development (particularly ventricular) Poor workload capacity (may indicate poor left ventricular function) Failure to achieve target heart rate (allowing for β blockers) • • • >1-mm down-sloping or planar ST-segment depression, 80 ms after the J point ST-segment elevation Failure to achieve 9 min of the Bruce protocol due to any of the points listed. Exercise tests have low specificity in the following situations (often as a result of resting ST-segment abnormalities): • • • • • • • • • Ischaemia in young women with atypical chest pains Atrial fibrillation LBBB WPW syndrome LVH Digoxin or β-blocker therapy Anaemia Hyperventilation Biochemical abnormalities such as hypokalaemia. 1.3.6 24-hour ambulatory blood pressure monitoring The limited availability and relative expense of ambulatory BP monitoring prevent its use in all hypertensive patients. Specific areas of usefulness include the following situations: • • • • • • Assessing for ‘white coat’ hypertension Borderline hypertensive cases who may not need treatment Evaluation of hypotensive symptoms Identifying episodic hypertension (eg in phaeochromocytoma) Assessing drug compliance and effects (particularly in resistant cases) Nocturnal BP dipper status (non-dippers are at higher risk). 1.3.7 Computed tomography Computed tomography (CT) has applications in anatomical (coronary arteries, chamber dimension, pericardium) and functional (contractility, ischaemia, viability) assessments of the heart. CT coronary angiography has gained considerable attraction in the identification of coronary artery disease, particularly in chest pain clinics and in some emergency departments following guidance from the National Institute for Health and Care Excellence (NICE). Calcium scores can be calculated quickly, with higher scores being more predictive of coronary obstruction. More detailed scanning allows coronary arteries to be identified and followed in two-dimensional cross-sections, as well as in three-dimensional reconstructions. This enables identification of lesions that appear obstructive. Increased speed, better ECG gating and higher-resolution scanners have meant that coronary arteries can be assessed with relatively low levels of radiation. The negative predictive value is higher than the positive predictive value; entirely normal scans are typically normal on invasive coronary angiography, whereas those with apparently more important disease may or may not have findings requiring action on invasive assessment. As such, CT coronary angiography is typically used when patients have a low pre-test likelihood of coronary disease, a negative effectively excluding the condition. CT pulmonary angiography (CTPA) is the gold standard investigation for: • • • • • • Pulmonary thromboembolic disease Anatomical assessment of the pericardium (eg in suspected constriction) Anomalous coronary artery origins (reliable imaging of the proximal third of major coronary arteries) Extramyocardial mediastinal masses Chamber dimensions Myocardial function, perfusion and ischaemia. 1.3.8 Magnetic resonance imaging Cardiac magnetic resonance imaging (MRI) is the gold standard technique for assessment of myocardial function, ischaemia, perfusion and viability, cardiac chamber anatomy and imaging of the great vessels. It has a useful adjunctive role in pericardial/mediastinal imaging. Limitations include its contraindication in patients with certain implanted devices (eg pacemakers) and time (consequently also cost), as a full functional study can take about 45 min. The contrast used (gadolinium), although not directly nephrotoxic, is subject to increased risk of metabolic toxicity in renally impaired individuals. Chief indications for cardiac MRI: • • • • • Myocardial ischaemia and viability assessment Differential diagnosis of structural heart disease (congenital and acquired) Chamber anatomy definition Initial diagnosis and serial follow-up of great vessel pathology (especially aortopathy) Pericardial and mediastinal structural assessment. 1.4 VALVULAR DISEASE AND ENDOCARDITIS 1.4.1 Murmurs Benign flow murmurs: soft, short systolic murmurs heard along the left sternal edge to the pulmonary area, without any other cardiac auscultatory, ECG or chest radiograph abnormalities. Thirty per cent of children may have an innocent flow murmur. Cervical venous hum: continuous when upright and is reduced by lying; occurs with a hyperdynamic circulation or with jugular vein compression. Large arteriovenous fistula of the arm: may cause a harsh flow murmur across the upper mediastinum. Effect of posture on murmurs: standing significantly increases the murmurs of mitral valve prolapse and HCM only. Squatting and passive leg raising increase cardiac afterload and therefore decrease the murmur of HCM and mitra valve prolapse, while increasing most other murmurs such as VSD, aortic, mitral and pulmonary regurgitation, and aortic stenosis. Effect of respiration on murmurs: inspiration accentuates right-sided murmurs by increasing venous return, whereas held expiration accentuates left-sided murmurs. The strain phase of Valsalva’s manoeuvre reduces venous return, stroke volume and arterial pressure, decreasing all valvular murmurs but increasing the murmur of HCM and mitral valve prolapse. Classification of murmurs • • • Mid-/late systolic murmurs • Innocent murmur • Aortic stenosis or sclerosis • Coarctation of the aorta • Pulmonary stenosis • HCM • Papillary muscle dysfunction • ASD (due to high pulmonary flow) • Mitral valve prolapse Mid-diastolic murmurs • Mitral stenosis or ‘Austin Flint’ murmur due to aortic regurgitant jet • Carey Coombs murmur (rheumatic fever) High AV flow states (ASD, VSD, PDA, anaemia, mitral regurgitation, tricuspid • regurgitation) • Atrial tumours (particularly if causing AV flow disturbance) Continuous murmurs • PDA • Ruptured sinus of Valsalva’s aneurysm • ASD • Large arteriovenous fistula • Anomalous left coronary artery • Intercostal arteriovenous fistula • ASD with mitral stenosis • Bronchial collaterals 1.4.2 Mitral stenosis Mitral stenosis (MS) is the thickening of the mitral leaflets that may occur at the cusps, commissures or chordal level, to cause an obstruction of blood flow from the left atrium to the left ventricle. Twothirds of patients presenting with this are women. The most common cause remains chronic rheumatic heart disease, which involves a sustained inflammatory reaction against the valve and valvular apparatus, due to antibody cross-reactivity to a streptococcal illness. Rarer causes include congenital disease, carcinoid, systemic lupus erythematosus (SLE) and mucopolysaccharidoses (glycoprotein deposits on cusps). Rheumatic heart disease originating in the UK is now exceptionally rare. A normal mitral valve has a valve area of 4–6 cm2: MS is diagnosed when the valve area is ≤2cm2: It is considered severe when ≤1cm2; symptoms are invariable and increased pulmonary pressures lead to pulmonary oedema, when heart rates increase, and pulmonary hypertension. Atrial fibrillation is invariable and increases thromboembolic stroke risk by 17×; anticoagulation is essential. Treatment can be percutaneous (balloon valvuloplasty) or surgical (limited mitral valvotomy – now rarely performed in developed nations – or open valve replacement). Features of severe MS • • • • • Symptoms • Dyspnoea with minimal activity • Haemoptysis • Dysphagia (due to left atrium enlargement) • Palpitations due to atrial fibrillation Chest radiograph • Left atrial or right ventricular enlargement • Splaying of subcarinal angle (>90°) • Pulmonary congestion or hypertension • Pulmonary haemosiderosis Echocardiogram • Doming of leaflets • Heavily calcified cusps • Direct orifice area >1.0 cm2 Signs • Low pulse pressure • Soft first heart sound • Long diastolic murmur and apical thrill (rare) • Very early opening snap, ie closer to S2 (lost if valves immobile) • Right ventricular heave or loud P2 • Pulmonary regurgitation (Graham Steell murmur) • Tricuspid regurgitation Cardiac catheterisation Pulmonary capillary wedge end diastole to left ventricular end-diastolic pressure (LVEDP) • gradient >15 mmHg • • • • LA pressures >25 mmHg Elevated right ventricular (RV) and pulmonary artery (P)A pressures High pulmonary vascular resistance Cardiac output <2.5 L/min per m2 with exercise Mitral balloon valvuloplasty Valvuloplasty using an Inoue balloon requires either a trans-septal or a retrograde approach, and is used only in suitable cases where echocardiography shows the following: • • • • The mitral leaflet tips and valvular chordae are not heavily thickened, distorted or calcified The mitral cusps are mobile at the base There is minimal or no mitral regurgitation There is no left atrial thrombus seen on TOE. 1.4.3 Mitral regurgitation The full structure of the mitral valve includes the annulus, cusps, chordae and papillary musculature, and abnormalities of any of these can cause regurgitation. The presence of symptoms and increasing left ventricular dilatation are indicators for surgery in the chronic setting. Surgical mortality rates are 2–7% for valvular replacements in patients with New York Heart Association (NYHA) grade II–III symptoms. Various techniques have revolutionised mitral valve surgery, transforming outcomes from being no better than medical therapy with replacement to almost normal with repair. In skilled surgical hands the repair is tailored to the precise anatomical abnormality. Functional mitral regurgitation (MR) is a term used to describe MR that is caused by stretching of the annulus secondary to ventricular dilatation. Main causes of MR • • • • • • • • Myxomatous degeneration Functional, secondary to ventricular dilatation Mitral valve prolapse Ischaemic papillary muscle rupture Congenital heart diseases Collagen disorders Rheumatic heart disease Endocarditis Indicators of the severity of MR • • • • • • Small-volume pulse Left ventricular enlargement due to overload Presence of S3 Atrial fibrillation Mid-diastolic flow murmur Precordial thrill, signs of pulmonary hypertension or congestion (cardiac failure). Signs of predominant MR in mixed mitral valve disease • • • Soft S1; S3 present Displaced and hyperdynamic apex (LV enlargement) ECG showing LVH and left axis deviation. Mitral valve prolapse This condition occurs in 5% of the population and is commonly over-diagnosed (depending on the echocardiography criteria applied). The patients are usually female and may present with chest pains, palpitations or fatigue, although it is often detected incidentally in asymptomatic patients. Squatting increases the click and standing increases the murmur, but the condition may be diagnosed in the absence of the murmur by echocardiography. Often there is myxomatous degeneration and redundant valve tissue due to deposition of acid mucopolysaccharide material. Mitral valve prolapse is usually eminently suitable for mitral valve repair, although this should be undertaken only if the severity of the regurgitation associated with the condition justifies it (see above). Several conditions are associated with mitral valve prolapse (see below), and patients with the condition are prone to certain sequelae. Sequelae of mitral valve prolapse: • • • • • Embolic phenomena Rupture of mitral valve chordae Dysrhythmias with QT prolongation Sudden death Cardiac neurosis. Conditions associated with mitral valve prolapse • • • • • • • • Coronary artery disease Polycystic kidney disease Cardiomyopathy – dilated cardiomyopathy/HCM Secundum ASD WPW syndrome PDA Marfan’s syndrome Pseudoxanthoma elasticum • • • • • Osteogenesis imperfecta Myocarditis SLE; polyarteritis nodosa Muscular dystrophy Left atrial myxoma 1.4.4 Aortic regurgitation Aortic regurgitation (AR) can occur due to disruption of the aortic valve or the aortic root. Either can occur acutely or chronically. Acute causes, including aortic dissection or valve rupture from endocarditis, present with acute decompensation and profound heart failure. Chronic causes allow time for the left ventricle to accommodate, with gradual enlargement of end-diastolic volumes. There are many echocardiographic criteria used to assess the severity of AR and none is ideal; they are usually used in combination with symptoms and LV dimensions. Causes of AR • • • • • • • • Valve inflammation • Chronic rheumatic • Infective endocarditis • Rheumatoid arthritis; SLE • Hurler’s syndrome Aortitis • Syphilis • Ankylosing spondylitis • Reiter’s syndrome • Psoriatic arthropathy Aortic dissection/trauma Hypertension Bicuspid aortic valve Ruptured sinus of Valsalva’s aneurysm VSD with prolapse of (right) coronary cusp Disorders of collagen • Marfan’s syndrome (aortic aneurysm) • Hurler’s syndrome • Pseudoxanthoma elasticum Eponymous signs associated with AR • • • • • • • • • Quincke’s sign – nail-bed fluctuation of capillary flow Corrigan’s pulse – (waterhammer); collapsing radial pulse Corrigan’s sign – visible carotid pulsation De Musset’s sign – head nodding with each systole Duroziez’s sign – audible femoral bruits with diastolic flow (indicating moderate severity) Traube’s sign – ‘pistol shots’ (systolic auscultatory finding of the femoral arteries) Austin Flint murmur – functional mitral diastolic flow murmur Argyll Robertson pupils – aetiological connection with syphilitic aortitis Müller’s sign – pulsation of the uvula Indications for surgery Acute severe AR will not be tolerated for long by a normal ventricle and therefore requires prompt surgery, except in the case of infection, where delay for antibiotic therapy is preferable (if haemodynamic stability allows). At 10 years, 50% of patients with moderate chronic AR are alive, but once symptoms occur deterioration is rapid. Features of AR indicative of the need for surgery • • • • • Symptoms of dyspnoea/LV failure • Reducing exercise tolerance Rupture of sinus of Valsalva’s aneurysm Infective endocarditis not responsive to medical treatment Enlarging aortic root diameter in Marfan’s syndrome with AR Enlarging heart • End-systolic diameter >55 mm at echo • Pulse pressure >100 mmHg • Diastolic pressure <40 mmHg • Lengthening diastolic murmur • ECG: lateral lead T-wave inversion Bicuspid valves The aortic valve is typically trileaflet, but can be congenitally bicuspid in 0.5–1% of the population. This abnormal valve has early onset degeneration with aortic stenosis presenting many years sooner than typical (40–50s versus 60–70s). In cases of biscuspid disease aortic regurgitation is more common. Bicuspid valves are also associated with an aortopathy and aortic root dilatation, which itself can lead to aortic regurgitation. 1.4.5 Aortic stenosis Aortic stenosis (AS) is generally caused by senile degeneration and thickening of normally thin pliable leaflets. A normal valve area is >2cm2 and severe AS typically has a valve area ≤1 cm2, with a mean pressure gradient of >40 mmHg on transthoracic echocardiography. The pressure gradient is dependent not only on the severity of the stenosis, but also on the speed that blood is pushed across the valve. This means that the pressure gradient can be reduced when LV function is impaired, or in MS or significant AR. In these cases, the dimensionless index, a ratio of aortic and LVOT velocities, can be useful (1 is normal, 0.25 severe). • • • • • • • Causes of AS: may be congenital bicuspid valve, degenerative calcification (common in elderly people) and post-rheumatic disease Subvalvular: causes of aortic gradients include HCM and subaortic membranous stenosis, whereas supravalvular stenosis is due to aortic coarctation, or Williams’ syndrome (with elfin facies, learning disability, hypercalcaemia) Sudden death: may occur in AS or subvalvular stenosis due to ventricular tachycardia. The vulnerability to ventricular tachycardia is due to LVH Complete heart block: may be due to calcification involving the upper ventricular septal tissue housing the conducting tissue. This can also occur post-operatively (after valve replacement) due to trauma Calcified emboli: can arise in severe calcific AS All symptomatic patients should be considered for surgery: surgical mortality rate for AS is predominantly related to the absence (2–8%) or presence (10–25%) of LV failure There is a strong association with ischaemic heart disease: 50% of AS patients have important coronary disease. Concomitant CABG should be considered at the time of valve replacement. Indicators of severe AS • • • • • • • • • Symptoms of syncope or LV failure Signs of LV failure Absent A2 Paradoxically split A2 Presence of precordial thrill S4 Slow-rising pulse with narrow pulse pressure Late peaking of long murmur Valve area >0.5 cm2 on echocardiography 1.4.6 Tricuspid regurgitation Tricuspid regurgitation (TR) is typically an inaudible murmur due to the low pressure in the right heart, but may have low frequency pansystolic murmur if right ventricular pressures are elevated. Other signs may be more prominent with an elevated JVP and giant c-V waves; a pulsatile liver edge may be palpable and peripheral oedema is invariable. Causes of severe TR include the following: • • • • • Functional, due to right ventricular dilatation (commonly coexists with significant MR) Infection: the tricuspid valve is vulnerable to infection introduced by venous cannulation (iatrogenic or through intravenous drug abuse) Carcinoid (nodular hepatomegaly and telangiectasia) Post-rheumatic Ebstein’s anomaly: tricuspid valve dysplasia with a more apical position to the valve. Patients have cyanosis and there is an association with pulmonary atresia or ASD and, less commonly, congenitally corrected transposition. 1.4.7 Prosthetic valves Valve prostheses may be metal or tissue. Mechanical valves are more durable but tissue valves do not require full lifelong anticoagulation. All valve replacements have a residual transvalvular gradient across them; for mechanical valves this can cause loud murmurs, eg an aortic valve replacement may still have a loud AS ejection systolic murmur. Mechanical valves There are many different types of mechanical valves. Common ones are: • • • Ball & Cage valve: e.g Starr–Edwards: ball and cage – ejection systolic murmur (ESM) in the aortic area and an opening sound in the mitral position are normal. These are the original mechanical valves, first implanted in 1961, and modified versions are still available Single tilting disc: Bjork–Shiley was the first, involving a single graphite disc coated in pyrolite carbon which tilts between struts of metal housing. A variation designed in the 1980s was prone to strut fracture with catastrophic embolisation and is now no longer manufactured. A modern variant includes the Medtronic Hall valve Bileaflet valves: two semicircular leaflets that open, creating a central and two peripheral orifices. Now the most commonly used valve type with many different manufacturers, including St Jude and the Sorin Carbomedics valve. Tissue valves • • Allografts: porcine or bovine three-cusp valve – 3 months’ anticoagulation sometimes recommended until tissue endothelialisation. No need for long-term anticoagulation if patient is in sinus rhythm Homografts: usually cadaveric and, again, need no long-term anticoagulation. Infection of prosthetic valves • • • • • • Mortality rate is still as high as 60% depending on the organism Within 6 months of implantation, it is usually due to colonisation by Staphylococcus epidermidis Septal abscesses may cause PR-interval lengthening Valvular sounds may be muffled by vegetations; new murmurs may occur Mild haemolysis can occur, and is detected by the presence of urobilinogen in the urine Dehiscence is an ominous feature requiring urgent intervention. Anticoagulation in pregnancy Warfarin may cause fetal haemorrhage and has a teratogenicity risk of 5–30%. This risk is dose dependent and abnormalities include chondrodysplasia, mental impairment, optic atrophy and nasal hypoplasia. The risk of spontaneous abortion may be increased. There is no agreed consensus on the ideal strategy: warfarin, unfractionated heparin and low-molecular-weight heparin all have advocates and detractors. 1.4.8 Infective endocarditis Clinical presentation Commonly presents with non-specific symptoms of malaise, tiredness and infective-type symptoms. Heart failure secondary to valvular regurgitation or heart block may also occur, as may an incidental presentation in the context of another primary infection. Signs of infective endocarditis As well as cardiac murmurs detected at auscultation, there are several other characteristic features of infective endocarditis: • • • • • • • • • Systemic signs of fever and arthropathy Hands and feet: splinter haemorrhages, Osler’s nodes (painful), Janeway’s lesions (painless) and clubbing (late); needle-track signs may occur in arm or groin Retinopathy: Roth’s spots Hepatosplenomegaly Signs of arterial embolisation (eg stroke or digital ischaemia) Vasculitic rash Streptococcus viridans (α-haemolytic group) are still the most common organisms, occurring in 50% of cases Marantic (metastatic-related) and SLE-related (Libman–Sacks) endocarditis are causes of noninfective endocarditis Almost any pathogenic organism may be implicated, particularly in immunocompromised patients. See also Section 1.4.7 on ‘Prosthetic valves’ and Table 1.4. Table 1.4 Infective endocarditis Groups affected by endocarditis Percentage of all cases of endocarditis Chronic rheumatic disease No previous valve disease Intravenous drug abuse Congenital defects Prosthetic 30 40 10 10 10 Management of infective endocarditis The aim of treatment is to sterilise the valve medically (usually 4–6 weeks of intravenous antibiotics), then assess whether the valvular damage sustained (eg degree of incompetence) or the risk of recurrence (eg if prosthetic valves) mandates surgical replacement. Earlier operations are undertaken only if clinically necessary as outcomes are poorer. • • Poor prognostic factors in endocarditis • Prosthetic valve • Staphylococcus aureus infection • Culture-negative endocarditis • Depletion of complement levels Indications for surgery • Cardiac failure or haemodynamic compromise • Extensive valve incompetence • Large vegetations • Septic emboli • Septal abscess • Fungal infection • Antibiotic-resistant endocarditis • Failure to respond to medical therapy Antibiotic prophylaxis The conditions listed in the next box are associated with an increased risk of endocarditis. • • • Acquired valvular heart disease with stenosis or regurgitation Valve replacement Structural congenital heart disease, including surgically corrected or palliated structural conditions, but excluding isolated ASD, fully repaired VSD or fully repaired PDA, and • • closure devices that are judged to be endothelialised Previous infective endocarditis HCM Antibiotic and chlorhexidine mouthwash prophylaxis is no longer recommended for dental procedures, endoscopies or obstetric procedures. Patients should be made aware of non-medical riskprone activities (eg intravenous drug use, piercings) and the symptoms of possible endocarditis. 1.5 CONGENITAL HEART DISEASE Causes of congenital acyanotic heart disease a • • With shunts • Aortic coarctation (with VSD or PDA) • VSD • ASD • PDA • Partial anomalous venous drainage (with ASD) Without shunts • Congenital AS • Aortic coarctation a Associated shunts Causes of cyanotic heart disease • • With shunts • Tetralogy of Fallot (VSD) • Severe Ebstein’s anomaly (ASD) • Complete transposition of great vessels (ASD, VSD/PDA) Without shunts • Tricuspid atresia • Severe pulmonary stenosis • Pulmonary atresia • Hypoplastic left heart 1.5.1 Atrial septal defect In ASDs, the interatrial septum may be defective or absent, allowing mixing of oxygenated and deoxygenated blood and shunting at the atrial level. The size of shunting and reduction in oxygenation will depend upon the size of the defect. ASDs are the most common congenital defects found in adulthood. Rarely, they may present as stroke in young people, due to paradoxical embolus that originated in the venous system and reached the cerebral circulation via right-to-left shunting. Fixed splitting of the second heart sound is the hallmark of an uncorrected ASD. There may be a left parasternal heave and a pulmonary ESM due to increased blood flow. There are three main subtypes: • • • Secundum (70%): central fossa ovalis defects often associated with mitral valve prolapse (10–20% of cases). ECG shows incomplete or complete RBBB with right axis deviation. Note that a PFO (slit-like deficiency in the fossa ovalis) occurs in up to 25% of the population, but this does not allow equalisation of atrial pressures, unlike ASD Primum (15%): sited above the AV valves, often associated with varying degrees of MR and TR and occasionally a VSD, and thus usually picked up earlier in childhood. ECG shows RBBB, left axis deviation and first-degree heart block. Associated with Down’s, Klinefelter’s and Noonan’s syndromes Sinus venosus (15%): defect in the upper septum, often associated with anomalous pulmonary venous drainage directly into the right atrium. Surgical closure is recommended with pulmonary: systolic flow ratios >1.5 : 1. Closure of secundum defects may be performed via cardiac catheterisation. Holt–Oram syndrome (triphalangeal thumb with ASD): a rare syndrome (autosomal dominant with incomplete penetration). It is associated with absence (or reduction anomalies) of the upper arm. Lutembacher’s syndrome: a rare combination of an ASD with mitral stenosis (the latter is probably rheumatic in origin). Investigations forASDs Right atrial and right ventricular dilatation may be seen on any imaging technique, as may pulmonary artery conus enlargement. Other characteristic features are: • • • Chest radiograph: pulmonary plethora Echocardiogram: paradoxical septal motion, septal defect and right-to-left flow of contrast during venous injection with Valsalva’s manoeuvre Catheterisation: pulmonary hypertension – raised right ventricular pressures and step-up in oxygen saturation between various parts of the right circulation (eg SVC to high right atrium). Treatment of ASD There is no specific medical therapy for ASDs; they are managed by either closure (percutaneous or surgical) or clinical and echocardiographic follow-up. Indications for closure: • • • • • • Symptoms (dyspnoea) Systemic embolism (typically stroke) Chamber dilatation Elevated right heart pressures Significant left-to-right shunt Systemic embolism (typically stroke). Patent foramen ovale A PFO is a channel within the interatrial septum, which is typically covered by a flap that opens to allow right-to-left communication when right-sided pressures elevate, such as when coughing or sneezing, or during Valsalva’s manoeuvre. During fetal development and while the placenta provides oxygenation, the interatrial septum allows communication through the foramen ovale. Upon birth, the reduction in resistance in lungs lowers right-sided pressure, and the septum primum shuts, sealing the foraman ovale. In a quarter of adults, this closure is incomplete allowing venous embolic material to cross into the arterial circulation. There may be a history of headaches, migraine or paradoxical embolism. Stroke may occur in young patients. PFOs are visualised on echocardiography using bubble contrast, by injecting agitated saline into a peripheral vein, which is then seen under echocardiography travelling from the right to the left atrium during Valsalva’s manoeuvre. Debate continues about the value of closing PFOs, which can be performed either percutaneously or surgically, but it may be considered according to the clinical scenario, and particularly after stroke in a young patient. 1.5.2 Ventricular septal defect The ventricular septum is made of two parts with a superior membranous component, which contains the AV node (AVN), and an inferior muscular component. Defects can occur in either. Most defects are small, requiring only conservative observation. VSDs are the most common isolated congenital heart defect (2/1000 births; 30% of all congenital defects). Membranous VSDs can be more complicated due to the AVN and proximity of the aortic apparatus. Spontaneous closure is more common in muscular defects but either can be closed by a percutaneous or surgical approach. Indications for closure • • • • • Significant left-to-right shunt Associated with other defect requiring cardiotomy Elevated right heart pressure causing pulmonary hypertension Endocarditis Membranous VSD causing AR • Large defects allow significant left-to-right shunt, causing elevated right heart pressures and consequent pulmonary hypertension Parasternal thrill and pansystolic murmur are present. The murmur may be ejection systolic in very small or very large defects. With large defects the aortic component of the second sound is obscured, or even a single/palpable S2 is heard; a mitral diastolic murmur may occur. The apex beat is typically hyperdynamic. • Once Eisenmenger’s complex develops, the thrill and left sternal edge (LSE) murmur abate and signs are of pulmonary hypertension regurgitation and right ventricular failure. Surgery should occur earlier to avoid this situation, otherwise a combined heart/lung transplantation would be required. • • Other cardiac associations of VSD • PDA (10%) • AR (5%) • Pulmonary stenosis • ASD • Tetralogy of Fallot • Coarctation of the aorta Types of VSD • Muscular • Membranous • AV defect • Infundibular • Into the right atrium (Gerbode’s defect) 1.5.3 Patent ductus arteriosus PDA is common in premature babies, particularly female infants born at high altitude, and also if maternal rubella occurs in the first trimester. The connection occurs between the pulmonary trunk and the descending aorta, usually just distal to the origin of the left subclavian artery. PDA often occurs with other abnormalities. Key features of PDA • • • • A characteristic left subclavicular thrill Enlarged left heart and apical heave Continuous ‘machinery’ murmur Wide pulse pressure and bounding pulse Signs of pulmonary hypertension and Eisenmenger’s syndrome develop in about 5% of cases. Indometacin closes the duct in about 90% of babies whereas intravenous prostaglandin E1 (PGE1) may reverse the natural closure (useful when PDA is associated with coarctation or hypoplastic left heart syndrome, and in complete transposition of the great vessels, because it will help to maintain flow between the systemic and pulmonary circulations). The PDA may also be closed thoracoscopically or percutaneously. 1.5.4 Coarctation of the aorta Coarctation is an aortopathy, a disease of the aorta, in which there is severe narrowing at the site of the regressed ductus arteriosus, which connects the aorta to the pulmonary artery in utero. If severe, aortic blood flow is impaired, causing heart failure and metabolic acidosis; it is life-threatening in early life. PGE1 can keep the ductus arteriosus patent to allow right-to-left shunting to the descending aorta while awaiting surgery. Milder coarctation may present beyond infancy with hypertension, leg cramps, muscle weakness and neurological changes. Pulses distal to the obstruction are diminished and delayed with lower blood pressure in the legs. Collateral development can be significant and audible posteriorly, and may cause ‘notching’ of ribs on chest radiographs. Barium swallows may demonstrate oesophageal compression from the post-stenotic dilatation of the aorta. Echocardiography may be sufficient but MRI is definitive. Treatment can be surgical or percutaneous. End-to-end anastomosis is the preferred surgical technique but re-stenosis can occur. Balloon dilatation of the coarctation is typically focused on recurrent coarctation after surgery. Complications may occur despite repair with 30% of patients with surgically corrected coarctation remaining significantly hypertensive with end-organ harm. Heart failure, re-coarctation at a new site in the aorta and aneurysm formation at the site of repair are other complications. Berry aneurysms and bicuspid aortic valves should be sought as there are strong associations with coarctation. Associations of coarctation • • • Cardiac • Bicuspid aortic valve (and thus AS ± AR) in 10–20% • PDA • VSD • Mitral valve disease Non-cardiac • Berry aneurysms (circle of Willis) • Turner’s syndrome • Renal abnormalities Signs of coarctation • Hypertension • • • • • • Radiofemoral delay of arterial pulse Absent femoral pulses Mid-systolic or continuous murmur (infraclavicular) Subscapular bruits Rib notching on chest radiograph Post-stenotic aortic dilatation on chest radiograph 1.5.5 Eisenmenger syndrome Eisenmenger syndrome refers to any untreated congenital cardiac defect with intracardiac communication that leads to severe irreversible pulmonary hypertension, reversal of left-to-right shunts, and cyanosis. Long-standing left-to-right shunts (eg in large VSDs, ASDs or PDAs) cause remodelling of the pulmonary microvasculature, with obstruction and pulmonary blood flow and raised pressures. This causes shunts to reverse, sending deoxygenated blood into the systemic circulation, which is evident as cyanosis. Signs of development include: • • • • • • Clubbing and central cyanosis Decrease of original pansystolic (left-to-right) murmur Decreasing intensity of tricuspid/pulmonary flow murmurs Single S2 with louder intensity, palpable P2; right ventricular heave Appearance of Graham Steell murmur due to pulmonary regurgitation Pansystolic murmur and v waves due to TR Eisenmenger syndrome • • Causes • VSD (Eisenmenger’s complex) • ASD • PDA Complications of Eisenmenger syndrome • Right ventricular failure • Massive haemoptysis • Cerebral embolism/abscess • Infective endocarditis (rare) 1.5.6 Tetralogy of Fallot The most common cause of cyanotic congenital heart disease (10%), usually presenting after age 6 months (as the condition may worsen after birth). Key features • • • • • Pulmonary stenosis (causes the systolic murmur) Right ventricular hypertrophy VSD Overriding of the aorta Right-sided aortic knuckle (25%) Clinical features • • • • • • • • Cyanotic attacks (pulmonary infundibular spasm) Clubbing Parasternal heave Systolic thrill Palpable A2 Soft ejection systolic murmur (inversely related to pulmonary gradient) Single S2 (inaudible pulmonary closure) ECG features of right ventricular hypertrophy Possible complications of Fallot’s tetralogy • • • • • • • • Endocarditis Polycythaemia Coagulopathy Paradoxical embolism Cerebral abscess Ventricular arrhythmias Fallot’s tetralogy is a spectrum disorder with clinical manifestations depending on the severity of the cardiac lesions. Typical presentation is with small for dates, difficulty feeding, failure to thrive and episodes of cyanosis when crying or feeding; clubbing is evident from 3–6 months Although classically considered to be only pulmonary stenosis, the principal lesion is right ventricular outflow tract obstruction, which can be valvular and/or infundibular. High-grade obstruction increases right-sided pressures, which may exceed LV pressure, promoting rightto-left shunting through the VSD, while simultaneously reducing pulmonary flow. Catecholamines and hypoxaemia trigger spasm of the infundibulum • • • Cyanotic episodes occur in infants, triggered by exercise, anxiety, dehydration, fever, anaemia, sepsis or spontaneously. The infant becomes inconsolable and cyanosis and tachypnoea ensues Cyanotic attacks worsen with catecholamines, hypoxia and acidosis. The murmur lessens or disappears as the right ventricular outflow gradient increases During cyanotic episodes, emergency treatment is necessary to avoid death. Parents should hold the infant against their shoulder, tucking the infant’s knees up; this increases systemic vascular resistance and reduces venous return of acidotic blood from the lower extremities, which reduces right ventricular infundibular spasm and right ventricular pressure, so breaking the cycle. In older children, squatting achieves this. Emergency treatment is necessary. • • • The presence of a systolic thrill and an intense pulmonary murmur differentiates the condition from Eisenmenger’s syndrome Traditionally, tetralogy of Fallot underwent a palliative procedure, such as the Blalock– Taussig shunt (the modern variant connects a graft between the subclavian artery and the pulmonary artery) with later complete resection. Modern practice favours total correction before 12 months. Infants may be stabilised on prostaglandins to maintain the patency of the ductus arteriosus and enable more elective surgery A Blalock-Taussigh shunt operation results in weaker pulses in the arm from which the subclavian artery is diverted to the pulmonary artery. 1.5.7 Important post-surgical circulations Systemic right ventricle Transposition of the great vessels and similar conditions in which the right ventricle supplies the aorta and the left ventricle supplies the pulmonary artery are now treated by arterial switch. Effectively this is a complete correction. Before the development of the arterial switch procedure, treatment was by ‘venous redirection’ – the vena cavae redirected via the atria to the left ventricle and the pulmonary veins to the right ventricle via the atria, with the morphological right ventricle then pumping oxygenated blood into the aorta. However, there was a high risk of ventricular dysfunction, valve regurgitation and ventricular arrhythmias in these patients, and decompensation would be provoked by development of atrial arrhythmias. Single ventricular circulation Individuals born with only one functional ventricle are treated by redirecting the vena cavae directly into the pulmonary arteries (total cavopulmonary correction) and now do very well. Early versions of this operation (the classic Fontan) used the right atrium between the vena cavae, but this often led to atrial dilatation and then fibrillation with a risk of decompensation. Common congenital circulations Common congenital circulations are summarised in Table 1.5. 1.6 ARRHYTHMIAS AND PACING Atrial fibrillation (AF) remains the most common cardiac arrhythmia, with incidence increasing with age (Framingham data indicate a prevalence of 76/1000 men and 63/1000 women aged 85–94 years). Atrial flutter frequently coexists with AF and, although it has a different immediate causal mechanism, it is a reflection of the same underlying disease. These arrhythmias assume particular significance because of the stroke risk associated with them. ‘SVT’ (supraventricular tachycardia) is the term usually used to indicate a presumed re-entry tachycardia involving the AV node or an accessory pathway. Ventricular tachycardia and ventricular fibrillation are life-threatening conditions, but there is a clear evidence base for the use of implantable cardioverter defibrillators in both primary and secondary prevention (see Appendix II). Antiarrhythmic drugs or catheter ablation may be useful adjuncts to treatment or, in some cases, they can be used as alternatives to defibrillators. 1.6.1 Bradyarrhythmias Any heart rate <60 beats/min is a bradycardia. A bradyarrhythmia is a pathological bradycardia. Bradyarrhythmias are considered according to their prognostic significance and symptomatic impact. High-grade AV block (Mobitz 2 or complete) is associated with sudden death and patients should be paced urgently even if asymptomatic. Permanent pacing is very effective in reducing symptoms in most bradyarrhythmias; the exception is neurocardiogenic syncope where the results are disappointing. Table 1.5 Common congenital circulations Common bradyarrhythmias and associated conditions Neurocardiogenic symptoms An exaggerated vasodepressor (hypotension), cardioinhibitory (bradycardic) or mixed reflex may cause syncope or presyncope. Various drugs have been tried as treatment, with limited success. In patients with a predominant cardioinhibitory component, dual-chamber pacing may reduce the severity and frequency of syncopal episodes but results are often disappointing. Sinus node disease Sinus bradycardia and sinus pauses can cause syncope, presyncope or non-specific symptoms. Thyroid function and electrolytes should be checked on presentation and corrected before considering pacemaker therapy. Pacing is indicated only in significantly symptomatic cases (as there is no prognostic benefit of pacing in sinus node disease). First-degree AV block A PR interval >200 ms is abnormal but usually requires no treatment. The combination of first-degree AV block with (1) LBBB, (2) RBBB with axis deviation, or (3) alternating LBBB and RBBB is interpreted as trifascicular block (more accurately, block in two fascicles and delay in the third). If associated with syncope, trifascicular block represents an indication for pacing on both prognostic and symptomatic grounds. Second-degree Mobitz I (Wenckebach’s) AV block Progressive prolongation and then block of the PR interval is categorised as Mobitz I. It may be normal during sleep and in young, physically fit individuals (who have high vagal tone). If it occurs when the patient is awake and is associated with symptoms in older people, pacing may be indicated on symptomatic grounds. High-grade AV block (second-degree Mobitz II block and third-degree complete heart block) Bradycardias with more than one P wave per QRS complex (second-degree Mobitz II) or with AV dissociation are grouped together as high-grade AV block. Untreated, they are associated with a mortality rate that may exceed 50% at 1 year, particularly in patients aged >80 years and in those with non-rheumatic structural heart disease. Pacing is indicated on prognostic grounds even in asymptomatic individuals. • Complete heart block is the most common reason for permanent pacing When related to an infarction, high-grade AV block occurs mostly with right coronary artery • occlusion, because the AV nodal branch is usually one of the distal branches of the right coronary artery In patients with an anterior infarct, high-grade AV block is a poor prognostic feature, indicating • extensive ischaemia Congenital cases may be related to connective tissue diseases; however, in patients with normal exercise capacities, recent studies show that the prognosis is not as benign as was previously • thought and pacing is therefore recommended in a wide range of circumstances (see European Society of Cardiology guidelines by Vardas et al Eur Heart J 2007;28:2256–95). Tachyarrhythmias Tachyarrhythmias are caused by re-entry, automaticity or triggered activity: Re-entry: the arrhythmia is anatomically dependent and usually the primary problem as opposed to sequelae of another reversible state Automaticity: arrhythmia is often secondary to a systemic cause (eg electrolyte imbalance, • sepsis, adrenergic drive) and is multifocal Triggered activity: shares features of both mechanisms and is seen in both primary arrhythmias • and drug toxicity. • 1.6.2 Supraventricular tachycardias There are two major groups of re-entrant tachycardias often described as SVT: AV nodal re-entry tachycardia (AVNRT; see Figure 1.6): involves a re-entry circuit in and around the AV node AV re-entry tachycardia (AVRT; see Figure 1.7): this involves an accessory pathway between • the atria and ventricles some distance from the AV node (eg WPW syndrome and related conditions). • AV nodal re-entry tachycardia Differential conduction in tissue around the AVN allows a micro re-entry circuit to be maintained (see Figure 1.6), resulting in a regular tachycardia. Accessory pathways An accessory pathway that connects the atrium and ventricle mediates the tachycardia by enabling retrograde conduction from ventricle to atrium. More seriously, the accessory pathway may predispose to unrestricted conduction of AF from atria to ventricles as a result of anterograde conduction through the pathway. This may lead to ventricular fibrillation. WPW is said to be present when a δ wave (partial pathway-mediated pre-excitation) is present on the resting ECG. Associations with WPW include: Ebstein’s anomaly (may have multiple pathways), HCM, mitral valve prolapse and thyrotoxicosis; it is more common in men. Some accessory pathways are not manifest by a δ wave on the resting ECG but are still able to participate in a tachycardia circuit. Atrial tachycardias, including flutter, AF, sinus tachycardia and fascicular ventricular tachycardia, may all be mistaken for SVT. Figure 1.6 Mechanism for atrioventricular nodal re-entry tachycardia Figure 1.7 Mechanism for atrioventricular re-entry tachycardia 1.6.3 Atrial arrhythmias Atrial flutter Atrial flutter involves a macro re-entrant circuit where the electrical activation circles the right atrium. This generates characteristic sawtoothed flutter waves, which typically have a rate between 250 and 350 beats/min, with a ventricular response of 150 beats/min (2 : 1 block). • • • • • The ventricular response may be slowed by increasing the vagal block of the AVN (eg carotid sinus massage) or by adenosine, which ‘uncovers’ the flutter waves on ECG This is the most likely arrhythmia to respond to DC cardioversion with low energies (eg 25 V) Amiodarone and sotalol may chemically cardiovert, slow the ventricular response or act as prophylactic agents Radiofrequency ablation is curative in up to 95% of cases Adenosine cannot terminate atrial flutter but can be useful in revealing it. Atrial flutter is described as typical when associated with a sawtooth atrial pattern in the inferior leads and positive flutter waves in V1. Atypical flutters tend to occur in congenital heart disease or after surgery or prior ablation. Atrial fibrillation This arrhythmia is due to multiple wavelet propagation in different directions. The source of the arrhythmia may be myocardial tissue in the openings of the four pulmonary veins, which enter into the posterior aspect of the left atrium, and this is particularly the case in younger patients with paroxysmal AF. AF may be paroxysmal, persistent (but ‘cardiovertable’) or permanent, and in all three states it is a risk factor for strokes. Treatment is aimed at ventricular rate control, cardioversion, prevention of recurrence and anticoagulation. Catheter ablation is indicated in symptomatic individuals who are resistant to, or intolerant of, medical therapy. With AF, a major decision is whether to control rate or alter the rhythm: Surprisingly, rhythm control does not reduce the risk of stroke (indeed paroxysmal AF carries the same stroke risk as chronic AF) and therefore does not affect the indications for anticoagulation • Cardioversions, multiple drugs and ablations are all used to alter rhythm • In asymptomatic individuals, rate control is recommended. • Associations with atrial fibrillation • • • • • • • • • • • • • • • • Ischaemic heart disease Pericarditis Mitral valve disease Pulmonary embolus Hypertension Atrial myxomas Thyroid disease LVH Acute alcohol excess/chronic alcoholic cardiomyopathy ASD Post-CABG Caffeine excess Dilated left atrium (>4.5 cm) Pneumonia WPW syndrome Bronchial malignancy The overall risk of systemic emboli is 5–7% annually (higher with rheumatic valve disease); this falls to 1.6% with anticoagulation. TOE may exclude atrial appendage thrombus but cannot predict the development of a thrombus in the early stages post-cardioversion; anticoagulation is therefore always recommended post-cardioversion. • Risk factors for stroke with non-valvular AF • • Previous history of cerebrovascular accident or transient ischaemic attack (risk × 22.5) • Diabetes (×1.7) • Hypertension (×1.6) • Heart failure Risk factors for recurrence of AF after cardioversion • Long duration (>1–3 years) • Rheumatic mitral valve disease • Left atrium size >5.5 cm • Older age (>75 years) • Left ventricular impairment The CHADS2 risk score has been modified to CHA2DS2-VASc and includes further risk factors (Tables 1.6 & 1.7). Previously, aspirin was considered a suitable alternative to warfarin in low-risk groups, but new studies suggest that the protective effect is minimal with only deleterious side-effects encountered. Therefore, warfarin is the agent of choice in most cases. Table 1.6 The CHA2DS2-VASc risk score CHA2DS2- VASc score Annual stroke risk (%/year) Suggested medication 0 1 2 3 4 5 6 7 8 9 0 1.3 2.2 3.2 4.0 6.7 9.8 9.6 6.7 15.2 Nil Aspirin or warfarin Warfarin Table 1.7 The CHA2DS2-VASc risk factors CHA2DS2-VASc risk factors Score Congestive heart failure Hypertension Age ≥75 Age 65–74 Diabetes mellitus 1 1 2 1 1 Stroke/TIA/thromboembolism Vascular disease Female gender 2 1 1 The HAS-BLED score (based on a mnemonic) helps consider a patient’s bleeding risks on anticoagulation (Table 1.8). Online calculators can estimate the bleeding risk. Table 1.8 The HAS-BLED score Letter Characteristics Definition Score H Hypertension Systolic BP >160 mmHg 1 A Abnormal renal and liver function Dialysis, renal transplantation or Cr >200 βmol/L; cirrhosis or 1 point each (1 or ALT/AST more than three times 2) upper normal limit S Stroke B Bleeding Previous bleeding or predisposition 1 to bleeding L Labile INRs INRs out of range >40% time E Elderly >65 years D Drugs or alcohol 1 1 1 Concomitant use of NSAIDs, 1 point each (1 or antiplatelet agents or alcohol abuse 2) ALT, alanine transaminase; AST, aspartate transaminase; Cr, creatinine; INRs, international normalised ratios; NSAIDs, non-steroidal anti-inflammatory drugs. 1.6.4 Ventricular arrhythmias and channelopathies Ventricular tachycardia (monomorphic) (Figure 1.8) VT has a poor prognosis when left ventricular function is impaired. After the exclusion of reversible causes such patients may need implantable defibrillators and antiarrhythmic therapy. • Ventricular rate is usually 120–260 beats/min Patients should be DC cardioverted when there is haemodynamic compromise; overdrive pacing • may also terminate VT Amiodarone, sotalol, flecainide and lidocaine may be therapeutic adjuncts or prophylactic • agents; magnesium may also be useful. Associations of VT • Myocardial ischaemia • Hypokalaemia or severe hyperkalaemia • Long QT syndrome (see below) • Digoxin toxicity (VT may arise from either ventricle, especially with associated hypokalaemia) • Cardiomyopathies Congenital abnormalities of the right ventricular outflow tract (VT with LBBB and right axis • deviation pattern) Features favouringVT in broad-complex tachycardia It is often difficult to distinguish VT from SVT with aberration (disordered ventricular propagation of a supraventricular impulse); VT remains the most common cause of a broad-complex tachycardia, especially with a previous history of MI. The following ECG observations favour VT: • Capture beats: intermittent sino-atrial (SA) node complexes transmitted to ventricle Fusion beats: combination QRS from SA node and VT focus meeting and fusing (causes cannon • waves) • RBBB with left axis deviation • Very wide QRS >140 ms • Altered QRS compared with sinus rhythm Figure 1.8 Ventricular tachycardia can feature fusion and capture beats. Mechanisms and example ECG patterns are shown • • • • • V lead concordance with all QRS vectors, positive or negative Dissociated P waves: marching through the VT History of ischaemic heart disease: very good predictor Variable S1 Heart rate <170 beats/min with no effect of carotid sinus massage. Note: none of the above has as high a positive predictive value for VT diagnosis as a history of structural heart disease (especially MI). Ventricular tachycardia (polymorphic) – torsades de pointes This is a particular type of VT in which the QRS complexes are of different amplitudes, appearing to ‘twist’ around the isoelectric line, with QT prolongation when the patient is in sinus rhythm. QT prolongation can be genetic (see below) or acquired – and can be of any cause to trigger torsades de pointes: Antiarrhythmic agents (particularly class III, such as sotalol) may predispose to torsades de • pointes by induced bradycardia and QT prolongation. Premature ventricular contraction (‘R-onT’ phenomenon) is more likely if the QT interval is very long, and can trigger torsades de pointes + • Intravenous magnesium and K channel openers may control the arrhythmia, whereas isoprenaline and temporary pacing may prevent bradycardia and hence the predisposition to VT. Pro-arrhythmic channelopathies Abnormally prolonged QT intervals may be familial or acquired, and are associated with syncope and sudden death, due to VT (especially torsades de pointes). Mortality in the untreated symptomatic patient with a congenital abnormality is high but some patients may reach the age of 50–60 years despite repeated attacks. Causes and associations are shown below. Pro-arrhythmic causes of abnormal repolarisation (ST – changes) • • • • • Familial • Long QT syndromes 1–5 • Brugada’s syndrome • Short QT syndrome • Arrhythmogenic right ventricular dysplasia Drugs • Quinidine • Erythromycin • Amiodarone • Tricyclic antidepressants • Phenothiazines • Probucol • Non-sedating antihistamines (eg terfenadine) Ischaemic heart disease Metabolic • Hypocalcaemia • Hypothyroidism • Hypothermia • Hypokalaemia Rheumatic carditis Long QT syndromes: the corrected QT is >540 ms (normal = 380–460 ms). Ninety per cent are familial, with chromosome 11 defects being common (Romano–Ward syndrome has autosomal dominant inheritance; Jervell–Lange–Nielsen syndrome is autosomal recessive and associated with congenital deafness). Arrhythmias may be reduced by a combination of β blockers and pacing. Cardiac causes of electromechanical dissociation When faced with a cardiac arrest situation it is important to appreciate the list of causes of electromechanical dissociation (EMD): • • • • • • • • Hypoxia Hypovolaemia Hypokalaemia/hyperkalaemia Hypothermia Tension pneumothorax Tamponade Toxic/therapeutic disturbance Thromboembolic/mechanical obstruction. 1.6.5 Pacing and ablation procedures Temporary pacing The pacing electrode is placed in the right ventricular apex causing activation from the right ventricle; as such the ECG will show LBBB morphology. If the pacing lead has perforated the septum, and entered the left ventricle, the morphology will show RBBB. Temporary pacing for emergencies such as heart block is typically ventricular only. Pacing post-cardiac surgery employs epicardial pacing wires, placed at the time of surgery, and this may be atrial or ventricular (atrial appendage and right ventricular apex) to optimise cardiac output. Complications include: Crossing the tricuspid valve during insertion, which causes ventricular ectopics, as does irritating the outflow tract • Atrial or right ventricular perforation and pericardial effusion Pneumothorax: internal jugular route is preferable to the subclavian one, because it minimises • this risk and also allows control after inadvertent arterial punctures. • Permanent pacing Permanent pacing can be ventricular only, or atrial and ventricular to preserve AV synchrony. The naming convention reflects the chamber paced, the chamber sensed and the pacemaker response to sensing, eg VVI means that the ventricle is paced and, when ventricular activity is sensed, the pacemaker inhibits itself. DDD is now increasingly used, with the device capable of ‘dual’ pacing, ‘dual’ sensing and ‘dual’ response to native cardiac beats (hence the term DDD). These capabilities mean much more sophisticated pacing behaviour can be programmed, such that different actions are taken in response to cardiac rhythms. For example, if the pacemaker detects activity in both atria and ventricles, it is inhibited and does nothing; alternatively if atrial activity is present but ventricular activity is absent, it will pace only the ventricle in time with the natural atrial activity. This allows sophisticated programming to optimise the device for the patient. Most pacemakers are now also rateresponsive (denoted by ‘R’); these use movement or physiological triggers (respiratory rate or QT interval) to increase heart rates. They reduce rates of pacemaker syndrome and act more physiologically for active patients. Pacemaker syndrome is a constellation of symptoms related to even subtle impairment of cardiac output or change in peripheral resistance caused by suboptimal pacemaker settings. Typically, it can be caused by subtle differences in atrioventricular synchrony which can cause loss of the atrial ‘kick’ (atrial contribution to cardiac output). Patients may be dizzy, hypotensive or develop signs of heart failure. Optimisation of pacemaker settings for the individual patient is now a routine clinical activity during pacemaker checks. Pacing in heart failure There are several synonymous terms for pacing in patients with cardiac failure. These include ‘cardiac resynchronisation therapy’, ‘biventricular pacing’ and ‘multisite pacing’. In heart failure pacing is indicated when all of the following are present: • NYHA III–IV heart failure • QRS duration >130 ms Left ventricular ejection fraction >35% with dilated ventricle and patient on optimal medical • therapy (diuretics, angiotensin-converting enzyme [ACE] inhibitors and β blockers). The atria and right ventricle are paced in the usual fashion and in addition to this a pacing electrode is placed in a tributary of the coronary sinus on the lateral aspect of the left ventricle. The two ventricles are paced simultaneously or near simultaneously with a short AV delay. The aim is to optimise AV delay and reduce inter- and intraventricular asynchrony. This therapy is known to reduce mortality, to improve exercise capacity, to improve quality of life and to reduce hospital admissions. Studies have not shown benefit in heart failure patients with narrow QRS duration, and echocardiographic markers of dyssynchrony are unreliable. A recent randomised study in which dyssynchrony markers were used to select patients for CRT instead of the traditional parameters showed no benefit and significant harm. Implantable cardioverter defibrillators Implantable cardioverter defibrillators (ICDs) are devices that are able to detect life-threatening tachyarrhythmias and terminate them by overdrive pacing or a counter-shock. They are implanted in a similar manner to permanent pacemakers. Current evidence supports their use in both secondary prevention of cardiac arrest and targeted primary prevention (eg for individuals with LV impairment and those with familial syndromes such as arrhythmogenic right ventricular dysplasia, Brugada’s syndrome, long QT variants). Radiofrequency ablation Radiofrequency ablation is resistive, heat-mediated (65°C) protein membrane disruption causing cell lysis. Using cardiac catheterisation (with electrodes in right- or left-sided chambers) it interrupts electrical pathways in cardiac structures. Excellent results are obtained in the treatment of accessory pathways and atrial flutter, and with complete AV nodal ablation or AV node modification. Ventricular tachycardia is technically more difficult to treat (ventricular myocardium is much thicker than atrial myocardium). Isolation of the pulmonary veins by ablation therapy is now an established technique to treat AF. Current cure rates are around 85%, but more than one procedure is required in half the cases. Complete heart block and pericardial effusions are rare complications of radiofrequency ablation. Indications to refer to an electrophysiologist Indications for referral to an electrophysiologist are given in Table 1.9. Table 1.9 Indications for referral to an electrophysiologist Condition When to refer Potential treatment SVT More than one episode Radiofrequency ablation Atrial flutter More than one episode Radiofrequency ablation Atrial fibrillation Highly symptomatic, refractory to Radiofrequency ablation or intolerant of drug therapy Ventricular fibrillation Unless there is an obvious reversible cause, eg ST-segment elevation MI (STEMI) ICD Ventricular tachycardia Unless obvious reversible cause Radiofrequency ablation or ICD Ischaemic cardiomyopathy Ejection fraction >30% on optimal medical therapy Primary prevention ICD NYHA class III–IV heart failure, QRS >130 ms, ejection fraction <35% On optimal medical therapy Heart failure pacing 1.7 ISCHAEMIC HEART DISEASE Ischaemic heart disease has been the leading worldwide cause of death since 1990, claiming 7 million lives a year. Risk factors for coronary artery disease • Primary • Hypercholesterolaemia (LDL) • Hypertension • Smoking Unclear • Low fibre intake • Hard water • High plasma fibrinogen levels • Raised Lp(a) levels • Raised factor VII levels Protective factors • Exercise • Moderate amounts of alcohol • Low cholesterol diet • Increased HDL:LDL Secondary • Reduced HDL-cholesterol • Obesity • Type 1 diabetes mellitus • Type 2 diabetes • Family history of coronary artery disease • Physical inactivity • Stress and personality type • Gout and hyperuricaemia • Race (Asians) • Low weight at 1 year of age • Male sex • Chronic renal failure • Increasing age • Low social class • Increased homocystine levels and homocystinuria • • • HDL, high-density lipoprotein; LDL, low-density lipoprotein. Smoking and its relationship to cardiovascular disease Smokers have an increased incidence of the following cardiovascular complications: • • • • Coronary artery disease Malignant hypertension Ischaemic stroke Morbidity from peripheral vascular disease • • • • Sudden death Subarachnoid haemorrhage Mortality due to aortic aneurysm Thromboembolism in patients taking oral contraceptives Both active and passive smoking increase the risk of coronary atherosclerosis by a number of mechanisms, including: • • • • • Increased platelet adhesion/aggregation and whole-blood viscosity Increased heart rate; increased catecholamine sensitivity/release Increased carboxyhaemoglobin level and, as a result, increased haematocrit Decreased HDL-cholesterol and vascular compliance Decreased threshold for ventricular fibrillation. 1.7.1 Angina Other than the usual forms of stable and unstable angina, those worthy of specific mention include: Decubitus: usually on lying down – due to an increase in LVEDP or associated with dreaming, cold sheets, or coronary spasm during rapid eye movement (REM) sleep Variant (Prinzmetal’s): unpredictable, at rest, with transient ST elevation on ECG. Due to • coronary spasm, with or without underlying arteriosclerotic lesions Syndrome X: this refers to a heterogeneous group of patients who have ST-segment depression on exercise testing but angiographically normal coronary arteries. The patients may have very• small-vessel disease and/or abnormal ventricular function. It is commonly described in middleaged women and oestrogen deficiency has been suggested to be an aetiological factor • Vincent’s angina: nothing to do with cardiology; infection of the pharyngeal and tonsillar space! • Causes of non-anginal chest pains • • • • • • Pericardial pain Aortic dissection Mediastinitis • Associated with trauma, pneumothorax or diving Pleural Usually with breathlessness in pleurisy, pneumonia, pneumothorax or a large peripheral • pulmonary embolus Musculoskeletal Gastrointestinal • Including oesophageal, gastric, gallbladder, pancreatic • • Hyperventilation/anxiety • Reproduction of sharp inframammary pains on forced hyperventilation is a reliable test Mitral valve prolapse • May be spontaneous, sharp, superficial, short-lived pain Symptomatic assessment of angina The Canadian cardiovascular assessment of chest pain is useful for grading the severity of angina: • • • • Grade I: angina only on strenuous or prolonged exertion Grade II: angina climbing two flights of stairs Grade III: angina walking one block on the level (indication for intervention) Grade IV: angina at rest (indication for urgent intervention). 1.7.2 Myocardial infarction Conservative estimates suggest there are 103 000 MIs per year in the UK with significant prehospital mortality, and a 5–6% inhospital mortality rate and a 6–7% 30-day mortality rate for those surviving to hospital admission. Overall, 19% of UK deaths are directly attributable to coronary disease. Acute coronary syndromes MI is part of the diagnostic entity now commonly referred to as ‘acute coronary syndrome’ (ACS). This overlapping constellation of conditions helps identify patients at risk and needing further treatment. The chest pain is typically retrosternal or heaviness, with radiation to the arms, neck or jaw. It can be intermittent or persistent. It may be associated with sweating, nausea, dyspnoea or syncope. These accessory symptoms are rare in stable angina, and that pain typically settles upon resting or with nitrates and has a predictable onset. The chest pain characteristic of an ACS is: • Prolonged (>20 min at rest) New-onset severe angina (Canadian Cardiovascular Society angina classification: Class III, • angina symptoms with everyday activities with moderate limitation) • Destabilisation ACS includes three distinct conditions: ST-elevation myocardial infarctions (STEMI), non-STelevation MIs (NSTEMIs) and unstable angina. The diagnosis for all three requires ECG changes and an appropriate history with typical corresponding features. An acute STEMI is when there is new ST-segment elevation (≥2 mm in two contiguous chest leads or ≥1 mm in two or more limbs). Posterior STEMI cause dominant R waves in V1 but will reveal ST elevation only if a posterior ECG is taken. New-onset LBBB with a typical history is also considered to be STEMI until proven otherwise. Patients are typically in pain, grey and sweaty. Most of those having STEMI have had prodrome symptoms in the previous weeks, with only a fifth having newonset symptoms for the last 24 hours. In STEMI, the vessel is typically entirely occluded by plaque rupture and subsequent thrombus formation. STEMI has the highest risk of inhospital mortality. NSTEMI includes ACS that features typical symptoms, ST depression, or new T-wave inversion and troponin rise. The spectrum of symptoms varies considerably. Patients’ risk may be assessed using GRACE or TIMI scores; most will receive dual antiplatelet therapy, together with statins and β blockers if appropriate. The majority of NSTEMI patients are managed invasively, typically having inpatient angiography and PCI. Vessels are less likely to be entirely occluded in NSTEMI but the presentation is variable. Approximately 10% of patients may be referred for CABG. Although patients can appear well, NSTEMIs have a higher mortality than STEMI at 12 months. Unstable angina refers to a sudden acceleration of anginal symptoms on minimal activity, either as new onset or on a background of stable angina. ECG changes may occur, but there is no troponin rise. Patients may be medically managed but those with higher risk characteristics may undergo invasive assessment. Diagnosis of MI Acute, evolving or recent MI Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: • • Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: • Ischaemic symptoms • Development of pathological Q waves on the ECG • ECG changes indicative of ischaemia (ST-segment elevation or depression) Pathological finding of an acute MI (eg postmortem). Established MI Any one of the following criteria satisfies the diagnosis of an established MI: Development of new pathological Q waves on serial ECGs. The patient may or may not • remember previous symptoms. Biochemical markers of myocardial necrosis may have normalised, depending on the length of time that has passed since the infarct developed • Pathological finding of a healed or healing MI Previous MI is also suggested when coronary artery disease and a regional ventricular wall • motion abnormality are seen, or characteristic myocardial scars are observed with MRI. Cardiac enzymes The widespread use of troponin assays has both simplified and lowered the bar for the diagnosis of MI. A number of markers of cardiac damage are now available. A number of markers of cardiac damage are available, the most popular being troponin which rises 3–12 hours after the event and falls over a week, and creatine kinase (with MB being the main isoenzyme), which rises and falls much more quickly. In general clinical practice, troponin is the mainstay for detecting myocardial damage. Consensus statements agree that troponin must rise over the 99th centile upper reference range, 12 hours after the episode of chest pain, together with symptoms and other features of ischaemia to diagnose myocardial infarction. Troponin is usually measured twice, on admission and at the 12-hour mark; it is this second troponin for which all study data is available. Troponin can be raised in other conditions (see below), and as such, it adds most clinical value when the pretest probability of MI or coronary artery disease is highest. The level of troponin is directly related to the amount of cardiac damage and is associated with the likelihood of later adverse outcomes. High-sensitivity troponin has recently been made available. These can measure low level troponin concentrations within the nanogram per litre range. These assays have revealed troponin is detectable in the plasma of healthy illness-free individuals. This means the specificity of the test has been reduced and leads to challenges in interpreting the results. The threshold for significance will depend upon the specific assay and manufacturer. Concerns include over-diagnosis of cardiac events with subsequent inappropriate investigation. The potential benefit is that high-sensitivity troponin assays can detect troponin rises more quickly after the index event, enabling the confirmed diagnosis to made on serial measurements performed within 2-3 hours of each other. Troponin rise in other conditions Troponin assays are now incredibly sensitive and can even detect fragments of the troponin molecule. Troponin is more closely linked to states of myocardial hypoperfusion rather than coronary occlusion as such, and it can leak from cardiomyocytes by any state that increases myocardial membrane permeability, even without true cell necrosis. There are a multitude of conditions that cause troponin leak (see box) and therefore high pretest probability, together with clear symptoms and new acute ECG changes, is mandatory to make a diagnosis of MI. Conditions that cause troponin leak • • • • • • • • • • Critical illness – intensive care unit/sepsis Hypotension Hypertensive crisis/pre-eclampsia Pulmonary embolism Infective exacerbations of COPD Abdominal aortic aneurysm rupture Gastrointestinal bleeding Chemotherapy: some directly cardiotoxic Renal impairment Neurological conditions: stroke, subarachnoid haemorrhage and seizures The advert of thrombolysis and then, primary percutaneous coronary intervention (PPCI) has greatly reduced complication rates. Late presentation (with completed infarctions) or failed PPCI in the STEMI setting is still associated with significant complications and the location of the infarct is related to the type seen. Troponin assays in patients with renal failure The troponin level may be elevated simply because a patient has renal failure. In patients with renal failure who present with chest pain, it is helpful to assess the troponin level at baseline as well as 12 h after the onset of symptoms, and sometimes at later time points. In these circumstances only a rising troponin level would be suggestive of ischaemic myocardial damage. Complications of MI Since the advent of thrombolysis, complication rates have been reduced (eg halved for pericarditis, conduction defects, ventricular thrombus, fever, Dressler’s syndrome). All complications may be seen with any type of infarction, but the following are the most common associations: • • Complications of anterior infarctions • Late VT/VF • Left ventricular aneurysm • Left ventricular thrombus and systemic embolism (usually 1–3 weeks post-MI)a • Complete heart block (rare) • Ischaemic mitral regurgitation • Congestive cardiac failure • Cardiac rupture – usually at days 4–10 with EMD • VSD with septal rupture Pericarditis and pericardial effusion (Dressler’s syndrome with high erythrocyte • sedimentation rate [ESR], fever, anaemia, pleural effusions and anti-cardiac muscle antibodies are seen occasionally) Complications of inferior infarctions • Higher re-infarction rate • Inferior aneurysm – with mitral regurgitation (rare) • Pulmonary embolism (rare) • Complete heart block and other degrees of heart block • Papillary muscle dysfunction and mitral regurgitation • Right ventricular infarcts need high filling pressures (particularly if posterior extension) a Although warfarin provides no general benefit, it may reduce the overall cerebrovascular accident rate (1.5–3.6%) in those patients with ECG demonstrable mural LV thrombus after a large anterior MI, so recommended for up to 6 months after the infarction. Heart block and pacing after MI Temporary pacing is indicated in anterior MI complicated by complete heart block. This presentation is associated with high mortality due to the extensive myocardial damage affecting the AVN. The right coronary artery is the dominant vessel (supplies the SA and AVN) in 85% of cases. Occlusion of the right coronary artery can cause complete heart block. The decision to temporarily pace a patient with inferior infarction is primarily dictated by the patient’s haemodynamic status. Atropine and isoprenaline may be used but most often rapid PPCI with restoration of blood flow to the right coronary artery will resolve heart block. A temporary pacing wire may be placed in the acute situation to provide cover. An observational period post-MI is appropriate to allow the return of sinus rhythm before considering permanent pacing. 1.7.3 PPCI for STEMI PPCI has replaced thrombolysis for most patients with STEMI in the UK. Centres providing PPCI services aim to take patients presenting within 12 hours of the onset of symptoms directly from the ambulance to the catheter laboratory, which has extensive resuscitation facilities, to reduce ‘door-toballoon’ times. An earlier invasive strategy is patients being assessed and, if meeting the diagnostic criteria of STEMI, will be consented for an immediate procedure. Urgent antiplatelets are given orally (aspirin 300 mg, and a second antiplatelet clopidogrel 600 mg, or prasugrel 60 mg or ticagrelor 180 mg), in addition to analgesia (Table 1.10). Arterial access is via the radial artery or femoral artery, and diagnostic angiographic images will typically reveal the occluded culprit vessel. Intraprocedure heparin or heparin-like drugs and/or bivalirudin (a direct thrombin inhibitor) may be used; adjunctive agents such as glycoprotein IIb/IIIa (GPIIb/IIIa) agents may be considered. If technically feasible, thrombus aspiration may be performed, but often flow is restored by the process of passing an intracoronary wire: this is accompanied by relief of pain and haemodynamic stabilisation. Culprit lesions are then stented, typically with the latest generation drug-eluting stents provided that there are no contraindications. Patients are cared for on a coronary care unit environment post-procedure. PPCI has the greatest value if performed early and should be considered in all patients presenting within 12 hours of pain. Those who present after 12 hours should also be considered if there is ongoing pain or ECG evidence of ongoing ischaemia. Thrombolysis Thrombolysis is still used in many clinical settings worldwide where access to PPCI is limited. It is most effective if given within 6 hours of symptom onset, with the greatest benefit seen in the highestrisk patients (STEMI). Multiple agents are available, including streptokinase, alteplase (tissue plasminogen activator or tPA), reteplase (recombinant or rPA) and tenecteplase (TNK-tPA). Recanalisation occurs in 70% of patients (compared with 15% without thrombolysis). Reperfusion arrhythmias (VTs and ectopics) are common in the first 2 hours after thrombolysis. Although now uncommon, examination questions may consider the contraindications to thrombolysis and these are given below. Contraindications to thrombolysis • Absolute contraindications • Active internal bleeding or uncontrollable external bleeding • Suspected aortic dissection • Recent head trauma (<2 weeks) • Intracranial neoplasms • History of proved haemorrhagic stroke or cerebral infarction <2 months earlier • Uncontrolled high BP (>200/120 mmHg) • • Pregnancy Relative contraindications • Traumatic prolonged cardiopulmonary resuscitation • Bleeding disorders • Recent surgery • Probable intracardiac thrombus (eg AF with mitral stenosis) • Active diabetic haemorrhagic retinopathy • Anticoagulation or international normalised ratio or INR >1.8 There is now a good evidence base for a range of pharmacological treatments in patients presenting with acute coronary syndromes (Table 1.10). These are aimed at dispersing clot (aspirin, clopidogrel, heparin), preventing arrhythmias (β blockers), stabilising plaque (statins) and preventing adverse remodelling. 1.7.4 Coronary artery interventional procedures Percutaneous coronary intervention PCI permits rapid and low-risk coronary revascularisation, which can be performed as an emergency (for STEMI), urgently (for NSTEMI or unstable angina) or electively (for stable angina, failed on medical therapy and with evidence of ischaemia). The principles are similar. Arterial access, either radial or femoral, permits catheter intubation of the coronary arteries and assessment of stenoses on fluoroscopy. Stenoses can be further assessed using imaging (to assess anatomical severity with IVUS or OCT) or functionally (to assess physiological significance of a stenosis using a pressure wire). Stenoses selected for intervention are then transversed using torquable intracoronary wires, before the stenosis is balloon-dilated and stented. Plain balloon angioplasty (POBA) is successful in relieving stenoses, but vessel recoil can cause acute occlusion which causes endothelial injury and triggers hyperplasia; this in turn leads to ‘restenosis’ – typically visible by 3 months. Bare-metal stents overcame these problems but can still undergo ‘instent re-stenosis’, where hyperplastic endothelium develops over the metal struts. This can be difficult to treat. Drug-eluting stents are coated in anti-mitotic agents to block smooth muscle and fibrous tissue proliferation and significantly reduce re-stenosis. However, this also means that metallic struts are exposed to blood for longer and dual antiplatelet therapy (typically aspirin and clopidogrel) is mandatory for 12 months. Lesions particularly amenable to PCI include those that are discrete, proximal, non-calcified, unoccluded, away from side branches and occur in patients with a short history of angina. • Although there is a small acute occlusion rate, these can usually be managed successfully with intracoronary stenting, such that the need for emergency CABG has fallen to <1% More challenging lesions include those within grafts, at bifurcations, calcified or long lesions, • and those within small vessels. People with diabetes have poorer outcomes compared with those who don’t have diabetes Almost any lesion can be stented, including left main stem disease, three-vessel disease and even • chronic total occlusions, but careful evaluation and discussion with the patient are necessary, as in many situations bypass grafting may offer patients greater freedom from repeat procedures and may have better prognostic outcome. Table 1.10 Summary of clinical trials in patients with acute myocardial infarction (MI)a Coronary artery bypass grafting CABG has benefits over coronary angioplasty in specific groups of patients with chronic coronary artery disease (when compared with medical therapy alone). Analysis has previously been limited because randomised trials included small numbers and were performed several decades ago; patients studied were usually men aged <65 years. The population now receiving CABG has changed, but so has medical therapy. The debate of CABG versus PCI is similarly complex. The recent FREEDOM trial compared CABG with PCI in people with diabetes with advanced coronary disease: they found that CABG had a superior reduction in a composite of mortality and myocardial infarction at 1 year compared with PCI. • • • • • Prognostic benefits are shown for symptomatic, significant left main stem disease (Veterans’ Study), symptomatic proximal three-vessel disease and two-vessel disease that includes the proximal left anterior descending artery (CASS data) Patients with moderately impaired LV function show greater benefit, but those with poor LV function have greater surgical mortality. Overall mortality rate is <2%, rising to between 5% and 10% for a second procedure. Eighty per cent of patients gain symptom relief Perioperative vein graft occlusion remains around 10%, with 1-2% per year for the next 6 years and then 5% per year thereafter. Intrathoracic arterial grafts (LIMA, RIMA) have much better patency, with some studies suggesting 98% patency at 10 years. However, occlusion rates vary considerably between studies and centres. On-pump and off-pump surgery and the use of adjuvant medications during the surgery contribute, as well as surgical technique A ‘Dressler-like’ syndrome may occur up to 6 months post-surgery Minimally invasive CABG involves the redirection of internal mammary arteries to coronary vessels without the need for cardiac bypass and full sternotomy incisions (often termed ‘offpump’ coronary revascularisation). Recovery times after this procedure are shorter than for conventional surgery but the procedures are technically more challenging Post-MI rehabilitation After MI, patients are typically kept in hospital for 5 days, but this will depend upon the management approach taken. Patients should usually take 2 months off work and have 1 month’s abstinence from sexual intercourse and driving (see following text). Cardiac rehabilitation is particularly important for patient confidence. Depression occurs in 30% of patients. Patients who are fully revascularised or invasively investigated and found to have no ongoing ischaemic focus may be discharged after 3 days and be rehabilitated more rapidly. Fitness to drive The DVLA (Driver and Vehicle Licensing Agency) provides extensive guidelines for coronary disease and interventions. Their website (www.dvla.gov.uk) should be consulted, especially with regard to class 2 licences (for vehicles >3500 kg, minibuses and buses) but the essential points are given in Table 1.11. 1.8 HEART FAILURE AND MYOCARDIAL DISEASES 1.8.1 Cardiac failure Cardiac failure can be defined as the pumping action of the heart being insufficient to meet the circulatory demands of the body (in the absence of mechanical obstructions). A broad echocardiographic definition is of an ejection fraction (EF) <40% (as in the SAVE trial, which enrolled patients for ACE inhibitors post-MI). Overall 5-year survival rate is 60% with EF <40%, compared with 95% in those with EF >50%. The most common single cause of cardiac failure in the Western world is ischaemic heart disease (IHD). • Hypertension is also a very frequent cause – either acting alone or in combination with IHD. Table 1.11 Fitness to drive Condition Driving restriction Notes Solitary loss of consciousness 6 months from last episode Clear vasovagal events that occur likely to be of cardiovascular or until effective treatment is only when the patient is erect do origin, but not confirmed, or likely given not preclude driving vasovagal syncope Cardiac catheter procedure (including angiography, percutaneous coronary 1 week intervention, electrophysiological studies/ablation) Should be able to perform emergency stop unhindered Myocardial infarction 1 month Permanent pacemaker 1 month Only 1 week if the patient has never been syncopal Prophylactic ICD 1 month No clinical arrhythmia or syncope Secondary prevention ICD 6 months DVLA must be informed ICD shock therapy 6 months Unless an inappropriate shock is preventable by reprogramming or intervention, eg a change in the detection or therapy programming to avoid shocks for sinus tachycardia or atrial arrhythmias DVLA, Driver and Vehicle Licensing Agency; ICD, implantable cardioverter defibrillator. EF is only a guide to cardiac function, which also depends on other factors including preload, afterload and tissue demand. However, EF is reduced in patients with systolic heart failure. • Preload: will affect LVEDP • Afterload: will affect LV systolic wall tension Other echocardiographic features of LV dysfunction include reduced fractional shortening, LV enlargement and paradoxical septal motion. The NYHA classification is a helpful indication of severity (Table 1.12). Heart Failure with Normal or Preserved Ejection Fraction (HF-PEF) Sometimes called ‘Diastolic Heart Failure’, this increasingly recognised condition should be considered in patients with breathlessness but no signs of fluid overload. It can overlap with systolic heart failure (being a concomitant problem) or be a distinct diagnosis. The principal problem is of impaired cardiac relaxation due to increased ventricular stiffness. This results in poor cardiac filling and elevated diastolic pressures in the heart and lungs causing dyspnoea. Patients will typically have elevated BNP levels, have no evidence of valve disease and have preserved systolic ejection fraction. Cardiac contractility may be reduced but since this is poorly reflected by the ‘ejection fraction’, then that itself may be within the normal range. The diagnosis is made using a number of echocardiographic volume and Tissue Doppler parameters that suggest it, but alone are not specific. A further difficulty is that some of these parameters change naturally with age and they are poorly reproducible over time, meaning there is no single parameter to confirm the diagnosis. Invasive tests and other imaging such as MRI have no role at present. Table 1.12 New York Heart Association (NYHA) classification of heart failure NYHA class Symptoms One-year mortality rate (%) I II III IV Asymptomatic with ordinary activity Slight limitation of physical activities Marked limitation of physical activities Dyspnoeic symptoms at rest 5–10 15 30 50–60 No treatment has been shown to reduce the morbidity or mortality in HF-PEF. Diuretics remain the mainstay, to reduce sodium and water retention and relieve dyspnoea. Controlling blood pressure and any ischaemia is important. Drug therapy for cardiac failure After diagnosis and during investigation for a cause of cardiac failure, drug therapy is commenced: • • • • • • • • • If oedema is present a loop diuretic is used (eg Furosemide). If no peripheral oedema is present, care must be taken to avoid hypovolaemia; prolonged use of loop diuretics is associated with increased mortality and they should be stopped where possible. If oedema persists despite good doses, consider diuretic resistance or poor absorption of drug. Limited data suggests bumetanide has better bioavailability due to better absorption. Alternatively, changing the route of administration (oral to IV bolus or infusion) can overcome resistance, or adding a thiazide diuretic (bendroflumetazide or metolazone). Note this last combination may trigger a significant diuresis and renal function may temporarily suffer. Nitrates give symptomatic benefit and may be needed in the acute phase of decompensation; longer term, a nitrate-free period should be maintained. Hydralazine is another vasodilator that appeared to show benefit when combined with nitrates in African-American heart failure patients (A-HeFT). This combination is often considered when impaired renal function precludes ACE inhibitors. ACE inhibitors should be started early and titrated up rapidly to the maximum tolerated dose (CONSENSUS, SOLVD and ATLAS studies showed significant improvements in mortality and morbidity). Angiotensin receptor blockers should be considered in ACE-inhibitor intolerant patients (eg cough). Val-HeFT, VALIANT and CHARM-added studies support their use. Note that they should not be used in combination with ACE inhibitors, as there is little additional benefit and harm may occur from worsening renal function. Beta blockers should be started once the patient is diuresed. Newer agents such as metoprolol, bisoprolol and carvedilol should be used. The majority of stable patients tolerate these well if started at low dose and up-titrated to the maximum dose. They achieve significant mortality and morbidity improvements (COPERNICUS, MERIT-HF, CIBIS-II). Beta blockers can be safely started in hospital in even those with recent decompensation. Cessation of previously stable ACE inhibitor and β-blocker therapy (eg when the patient is admitted with intercurrent infection with hypotension and/or acute renal impairment) is associated with increased mortality. These drugs should be continued unless profoundly hypotensive, or at least restarted after clinical stability has been restored. Aldosterone receptor antagonists: Spironolactone and eplerenone should be added if patients continue to have symptoms despite ACE inhibitors and β blockers. RALES (spironolactone) and EMPHASIS-HF (eplerenone) both showed significant mortality and morbidity benefit in severe HF. Eplerenone is additionally indicated in patients who suffer heart failure after myocardial infarction (EPHESUS). Observe for hyperkalaemia and impaired renal function. Ivabradine is a rate-limiting drug with a novel mode of action, selectively inhibiting the I f channel in the sinus node, to slow the sinus rhythm (but not arrhythmias). It has use-dependency meaning faster heart rates are most effected. The SHIFT study showed ivabradine added to HF patients with HR ≥70 bpm, despite other optimal medical therapy, reduced a composite of cardiovascular mortality and admission. It is recommended β blockers are at maximal doses before ivabradine is considered. Digoxin may help improve symptoms in patients with systolic heart failure and sinus rhythm. A • single study, DIG, did not show a mortality benefit but showed reduction in hospitalisation. However this was before the β-blocker era and digoxin should only be considered once other therapies are maximal. Omega-3 polyunsaturated fatty acids (Omacor): these are purified fatty acids at high dose without the characteristic taste of fish oils. In the GISSI-HF PUFA study, patients randomised to • these drugs had a just-significant reduction in cardiovascular mortality, felt to be due to reduction in arrhythmias. Heart failure patients should avoid glitazones (eg rosiglitazone and pioglitazone), calcium • channel blockers (diltiazem, verapamil), NSAIDs and COX-2 inhibitors, since all cause worsening of fluid retention and heart failure. Summary of therapeutic interventions in heart failure A summary of therapeutic interventions in heart failure is given in Table 1.13. Table 1.13 Summary of therapeutic interventions in heart failure Intervention Benefit Diuretics Symptom control ACE inhibitors Mortality and symptoms Angiotensin receptor blockers Mortality and symptoms β blockers Mortality and symptoms Aldosterone antagonists Ivabradine Digoxin Vasodilators Cardiac resynchronisation therapy Implantable cardioverter defibrillator Mortality and symptoms Mortality and symptoms Symptom control Symptom control Anticoagulation Comment Loop diuretic or loop diuretic with thiazide Should be titrated to maximum tolerated dose In place of or in addition to ACE inhibitors Bisoprolol and carvedilol have the best evidence base NYHA III–IV NYHA II–IV NYHA III–IV Mortality and symptoms NYHA III–IV, see Section 1.6.5 Mortality See Section 1.6.5 Stroke morbidity In AF or if there are prior thromboemboli ACE, angiotensin-converting enzyme; AF, atrial fibrillation; NYHA, New York Heart Association. 1.8.2 Hypertrophic cardiomyopathy HCM is a spectrum disorder with a diverse range of gene mutations that lead to myocardial disarray and hypertrophy. The hypertrophy can be apical, global or predominantly in the outflow tract. There is dynamic outflow tract obstruction, which causes an audible ESM and accounts for exertional symptoms and risk of sudden death. Characteristic features of HCM • • • • • • • Jerky pulse with large tidal wave as outflow obstruction is overcome Large a waves in the JVP Double apical impulse (palpable atrial systole, S4, in sinus rhythm) LSE systolic thrill (turbulence) with harsh ESM radiating to axilla Often accompanied by mitral regurgitation Often paradoxical splitting of second heart sound The ESM increases with Valsalva’s manoeuvre and decreases with squatting. Important points to remember • • • • • • • • • Autosomal dominant in half the patients, associated with chromosomes 1, 11, 14 or 15. May also result from a gene mutation that leads to myocardial disarray and varying expression of hypertrophy. Prevalence <0.2% in the general population. Life expectancy is variable and the risk of sudden cardiac death (SCD) can be estimated from the presence of family history of SCD, severe symptoms including prior cardiac arrest or unexplained syncope, and key findings on investigation (including: non-sustained ventricular tachycardia on holter monitoring, severe LVH with wall thickness >30mm, BP fall during exercise) Associations with Friedreich’s ataxia, WPW, phaeochromocytoma, familial lentiginosis ESM increases with: glyceryl trinitrate (GTN), digoxin and standing, due to volume reduction in diastole; ESM decreases with: squatting, βblockers, Valsalva’s release, handgrip Cardiac catheterisation abnormalities include a ‘banana’ or ‘spade-shaped’ LV cavity in systole, MR and ‘swordfish’ narrowing of the left anterior descending artery Therapeutic options include β blockers, calcium antagonists, amiodarone, dual-chamber pacing, internal defibrillators, surgical myomectomy or therapeutic septal infarction Avoid digoxin (if in sinus rhythm), nitrates, atropine, inotropes, diuretics (unless in left ventricular failure) Sudden death may be due to catecholamine-driven extreme outflow obstruction, VF related to accessory pathway-transmitted AF, or massive MI. Sudden death may occur without hypertrophy. Annual mortality rate of 2.5% in adults and 6% in children Poor prognostic features include young age at diagnosis, family history of sudden death and syncopal symptoms, but there is no correlation with the LVOT gradient Pregnancy is possible, but haemorrhage, prolonged vaginal delivery effort and epidural analgesia are best avoided; antibiotic prophylaxis and counselling are advised. 1.8.3 Dilated cardiomyopathy Dilated cardiomyopathy (DCM) is a syndrome of global ventricular dysfunction and dilatation, usually with macroscopically normal coronary arteries (if causes of ischaemic cardiomyopathy are excluded). The aetiology is often undetermined and the condition is more common in male and African-Caribbean patients (this association is possibly because of undiagnosed hypertensive cardiomyopathy). There is often LBBB or poor R-wave progression on ECG, and anticoagulation may be warranted as the incidence of AF and ventricular thrombus is high. DCM is treated as other forms of cardiac failure, with ACE inhibitors and βblockers, with escalating therapies, including cardiac resynchronisation therapy, as the NYHA class worsens. Causes of DCM • • • • • • • • • • Alcohol Undiagnosed hypertension Autoimmune disease Nutritional deficiency (eg thiamine and selenium) Muscular dystrophies Viral infections (eg Coxsackie virus and HIV) Peripartum Drugs (eg doxorubicin) Infiltration (eg haemochromatosis, sarcoidosis) Tachycardia-mediated cardiomyopathy (uncontrolled fast heart rates, eg AF) Diabetes – combination of epicardial coronary disease, microvascular ischaemia, metabolic • derangement of myocyte function 1.8.4 Restrictive cardiomyopathy This produces identical symptoms to constrictive pericarditis (see Section 1.9.1) but surgery is of little use in restrictive cardiomyopathy. The ventricles are excessively rigid and impede diastolic filling. AF may supervene and stagnation of blood leads to thrombus formation. • • Myocardial causes • Idiopathic • Scleroderma • Amyloid (see below) • Sarcoid • Haemochromatosis • Glycogen storage disorders • Gaucher’s disease Endomyocardial causes • Endomyocardial fibrosis • • • • Hypereosinophilic syndromes (including Löffler’s) Carcinoid Malignancy or radiotherapy Toxin-related Cardiac amyloidosis Cardiac amyloidosis is caused by extracellular deposition of insoluble amyloid fibrils. The protein deposition can be due to a primary disorder (AL amyloidosis, a clonal plasma cell disorder with light chain production to form the fibrils) or a secondary disorder (any chronic inflammatory disorder). The deposition and resultant fibrosis cause the ventricles to become thickened and stiff, with poor systolic and diastolic function. The atria typically dilate in response and may develop AF. Infiltration of the conducting tissues leads to heart block. ECGs characteristically have low-voltage QRS complexes and the echocardiographic appearances of the myocardium are classically ‘speckled’. Diagnosis can be confirmed by rectal biopsy with Congo red staining, which can demonstrate amyloid infiltration. Cardiac involvement is a marker of poor prognosis in amyloid disease, with congestive heart failure, syncope, pulmonary hypertension and conduction problems being causes of death. Treatment is palliative. Negative inotropic drugs (eg diltiazem) must be avoided and care taken with digoxin, which binds avidly to the fibrils and can reach toxic levels even within the therapeutic range. 1.8.5 Myocarditis Myocarditis may be due to many different aetiological factors (eg viral, bacterial, fungal, protozoal, autoimmune, allergic and drugs). It may be difficult to differentiate from DCM, but the following features may help: • • • • • • • • Usually a young patient Acute history Prodrome of fever, arthralgia, respiratory tract infection, myalgia Neutrophilia Slight cardiomegaly on chest radiograph Episodes of VT, transient AV block and ST/T-wave changes Elevated viral titres Cardiac enzymes raised (with normal coronary arteries). Myocarditis is associated with severe morbidity and mortality and needs careful support and management in the intensive care environment. Transplantation may be necessary if there is poor response to therapy. Those who recover may be left with significant cardiac impairment. Rheumatic fever This follows a group A streptococcal infection; pancarditis usually occurs and valvular defects are long-term sequelae. The cardiac histological marker is Aschoff’s nodule. Patients are treated with penicillin and salicylates or steroids. Criteria for diagnosis include the need for evidence of preceding α-haemolytic streptococcal infection (raised antistreptolysin O titre [ASOT], positive throat swab or history of scarlet fever), together with two major (or one major and two minor) Duckett–Jones criteria (see below). Rheumatic fever (Duckett–Jones diagnostic criteria) • • Major criteria • Carditis • Polyarthritis • Chorea • Erythema marginatum • Subcutaneous nodules Minor criteria • Fever • Arthralgia • Previous rheumatic heart disease • High ESR and C-reactive protein (CRP) • Prolonged PR interval on ECG 1.8.6 Cardiac tumours Myxomas are the most common cardiac tumours, comprising 50% of most pathological series. Atrial myxomas • • • • • Post-mortem incidence of <0.3%; more common in females (2 : 1) and in the left atrium (75% of myxomas); usually benign and occasionally familial Signs: fever and weight loss occur in 25%, and this may be due to release of interleukin-6 (IL-6). There may be transient mitral stenosis, early diastolic ‘plop’, clubbing, Raynaud’s phenomenon (rare) or pulmonary hypertension. Usually the rhythm is sinus. Atrial myxomas may present with the classic triad of systemic embolism, intracardiac obstruction and systemic symptoms Investigations: white cell count high, platelets low, haemolytic anaemia or polycythaemia, raised immunoglobulins, raised ESR in 60% (thought to be due to secretion of IL-6) Avoid left ventricular catheterisation; use TOE to diagnose. They occur most commonly on the interatrial septum Atrial myxomas grow rapidly with a risk of embolisation and sudden death, so they should be resected surgically without delay. Other primary cardiac tumours These include papillomas, fibromas, mesotheliomas, which are all rare lesions. 1.8.7 lipomas, angiosarcomas, rhabdomyosarcomas and Alcohol and the heart Acute alcoholic intoxication is the most common cause of paroxysmal AF among younger individuals. Chronic excessive intake over 10 years is responsible for a third of the cases of DCM in Western populations; alcohol is also aetiologically related to hypertension, cerebrovascular accident (CVA), arrhythmias and sudden death. AF may be the first presenting feature (usually between the ages of 30 and 35 years). Pathological mechanisms • • • • Direct myocardial toxic effect of alcohol and its metabolites Toxic effect of additives (eg cobalt) Secondary effect of associated nutritional deficiencies (eg thiamine) Effect of hypertension Treatment includes nutritional correction and – most importantly – complete abstinence from alcohol, without which 50% will die within 5 years. Abstinence can lead to a marked recovery of resting cardiac function. Beneficial mechanisms of modest amounts of alcohol • • • • • Favourable effects on lipids (50% of this benefit is due to raised HDL levels) Antithrombotic effects (perhaps by raising natural levels of tissue plasminogen activator) Antiplatelet effects (changes in prostacyclin:thromboxane ratios) Increase in insulin sensitivity Antioxidant effects of red wine (flavonoids and polyphenols) 1.8.8 Cardiac transplantation Six UK centres currently conduct heart transplantations with approximately 150 operations carried out per year, most often for intractable coronary disease and cardiomyopathy (44%); survival rates have been estimated at 80% at 1 year, 75% at 3 years and 40–50% at 10 years. Myocarditis is yet another indication; transplantation during the acute phase does not worsen prognosis, but myocarditis may recur in the donor heart. The major complications encountered after transplantation include accelerated coronary atheroma, lymphoma, skin cancer (and other tumours) and chronic kidney disease (due to ciclosporin A or tacrolimus toxicity). 1.9 PERICARDIAL DISEASE 1.9.1 Constrictive pericarditis Rare in clinical practice, this presents in a similar way to restrictive cardiomyopathy, ie with signs of right-sided heart failure (cachexia, hepatomegaly, raised JVP, ascites and oedema) due to restriction of diastolic filling of both ventricles. It is treated by pericardial resection. Other specific features include: • • • • A diastolic pericardial knock occurs after the third heart sound, at the time of the y descent of the JVP, and this reflects the sudden reduction of ventricular filling – ‘the ventricle slaps against the rigid pericardium’ Soft heart sounds and impalpable apex beat Severe pulsus paradoxus occurs rarely and indicates the presence of a coexistent tense effusion Thickened, bright pericardium on echocardiography. Causes of constrictive pericarditis • • • • • • • • • Tuberculosis (usually post-pericardial effusion) Mediastinal radiotherapy Pericardial malignancy Drugs (eg hydralazine, associated with a lupus-like syndrome) Post-viral (especially haemorrhagic) or bacterial pericarditis Following severe uraemic pericarditis Trauma/post-cardiac surgery Connective tissue disease Recurrent pericarditis Signs common to constrictive pericarditis and restrictive cardiomyopathy • • • • Raised JVP with prominent x + y descents AF Non-pulsatile hepatomegaly Normal systolic function Some key features distinguish constrictive pericarditis from restrictive cardiomyopathy: • Absence of LVH in constrictive pericarditis • Absent calcification on chest radiograph, prominent apical impulse and conduction abnormalities on ECG, which are features of restrictive cardiomyopathy. However, a combination of investigations, including cardiac CT, MRI and cardiac biopsy, may be necessary to differentiate between the two conditions. 1.9.2 Pericardial effusion A slowly developing effusion of 2 L can be accommodated by pericardial stretching and without raising the intrapericardial pressure. The classic symptoms of chest discomfort, dysphagia, hoarseness or dyspnoea (due to compression) may be absent. A large effusion can lead to muffled heart sounds, loss of apical impulse, occasional pericardial rub, small ECG complexes and eventually EMD. Other key features are: • Pulsus alternans: variable left ventricular output and right ventricular filling Pulsus paradoxus: exaggerated inspiratory fall in systolic BP (mechanism described in section • 1.2.2) • Electrical alternans on ECG: ‘swinging QRS axis’ • Globular cardiac enlargement on chest radiograph Causes of pericardial effusion • • • • • All causes as listed for constrictive pericarditis Aortic dissection Iatrogenic due to pacing or cardiac catheterisation Ischaemic heart disease with ventricular rupture Anticoagulation associated with acute pericarditis 1.9.3 Cardiac tamponade In contrast, if a small amount of intrapericardial fluid (eg <200 mL) accumulates rapidly, it can significantly limit ventricular filling, reduce cardiac output and elevate intracardiac pressures (particularly right sided initially). Thus the y descent due to right ventricular filling with tricuspid valve opening is lost as right ventricular pressures are high, and the x descent of right atrium filling due to right ventricular contraction is prominent. The right atrium collapses in diastole as a result of impaired filling and high intrapericardial pressures. In early diastole even the right ventricle may collapse. Occasionally the stretched pericardium may compress the lingular lobe of the left lung, causing bronchial breathing at the left base (Ewart’s sign). The QRS axis of the ECG may also be altered (electrical alternans). Common signs of cardiac tamponade • • • • • • • • Elevated jugular venous pressure Kussmaul’s sign Tachypnoea Systolic hypotension Pulsus paradoxus Tachycardia Diminished heart sounds Impalpable apex beat Treatment is by urgent drainage – usually under echocardiographic control. Surgical ‘pericardial’ windows may be necessary for chronic (eg malignant) effusions. 1.10 DISORDERS OF MAJOR VESSELS 1.10.1 Pulmonary hypertension It is important to determine whether pulmonary hypertension is secondary to an underlying condition because this may be treatable. The most common cause of secondary pulmonary hypertension is COPD. WHO Venice classification of pulmonary hypertension WHO group 1: pulmonary arterial hypertension • • • • • • • • Idiopathic/Sporadic Familial Associated with pulmonary venous or capillary disease Associated with systemic diseases: • Collagen vascular disease (eg scleroderma) • HIV Drugs/Toxins (eg anorexigens) Portal hypertension Congenital heart disease with shunting left to right (ASD, VSD) Persistent pulmonary hypertension of newborn babies WHO group 2: pulmonary hypertension associated with left heart disease • Atrial or ventricular disease (DCM, IHD, HCM) • Valvular disease (eg MS) • Extrinsic compression of the central pulmonary veins WHO group 3: pulmonary hypertension associated with lung diseases and/or hypoxemia • • • • • • COPD Interstitial lung disease Obstructive sleep apnoea Alveolar hypoventilation disorders Chronic high altitude Chronic hypoxia (polio, myasthenia) WHO group 4: pulmonary hypertension due to chronic thrombotic and/or embolic disease • • • • • Pulmonary emboli of proximal arteries Obstruction of distal pulmonary arteries Embolisation of thrombus, tumour, ova, parasites or foreign material In situ thrombosis Sickle cell disease WHO group 5: pulmonary hypertension caused by disorders directly affecting the pulmonary vasculature • Inflammatory – schistosomiasis, sarcoidoisis • Pulmonary capillary haemangiomatosis Primary pulmonary hypertension Primary pulmonary hypertension (PPH) is a rare disease with an incidence of 2/million per year; it is a disease of children and young adults, with a female:male ratio of 2 : 1. PPH constitutes <1% of all cases of pulmonary hypertension and is characterised by a mean pulmonary artery pressure >25 mmHg at rest, in the absence of another demonstrable cause. One in ten cases is familial. PPH is associated with connective tissue disease, vasculitis and HIV infection, and also the use of appetite suppressants (eg fenfluramine). The pulmonary arteries become dilated and abnormally thickened; there is dilatation of the proximal pulmonary vessels with thick-walled, obstructed, ‘pruned’ peripheral vessels. As a consequence of the high pulmonary pressure the right ventricle undergoes marked hypertrophy. Patients present with gradually worsening exertional dyspnoea and, in the later stages, angina of effort and syncope occur. Fatigue is common and haemoptysis may occur. • Signs include: cyanosis, right ventricular heave, loud P2, tricuspid regurgitation, peripheral oedema and ascites Diagnosis may be suggested on echocardiography with dilated right ventricle with impaired • function; estimated pulmonary pressures will be elevated. Confirmation requires cardiac catheterisation and direct measure of mean pulmonary arterial pressure (>25 mmHg), in the presence of normal wedge pressure (≤15 mmHg) • Untreated, the median survival is approximately 3 years. Treatment of PPH This would usually be undertaken at a specialist centre. The chief aspects involve: • • • • • • • Advise avoidance of strenuous exercise and recommend contraception, because pregnancy is harmful Anticoagulation to avoid thrombus formation in situ in the pulmonary arteries and also pulmonary embolism Prostacyclin (PGI2), a potent pulmonary and systemic vasodilator, is used, particularly to bridge patients to transplantation. The drug has an extremely short half-life and has to be given by continuous intravenous infusion, usually through a tunnelled central venous catheter. It is also very expensive Endothelin receptor blockade (eg bosentan) Calcium channel antagonists have been used to lower pulmonary (and systemic) pressure Diuretics are helpful in the management of right heart failure Continuous ambulatory inhaled nitric oxide is being developed, and this would provide good pulmonary vasodilatation, but without systemic effect. The chief therapeutic option is transplantation, because other treatments are of limited benefit or are difficult to administer. Summary of available treatments for pulmonary hypertension • • • General • Address secondary causes where possible • Digoxin, even in patients with sinus rhythm • Diuretics for symptoms • Ambulatory supplemental oxygen for some • Anticoagulation Vasodilator therapy (only helps some patients) • Endothelin receptor blockers (eg bosentan) • PGI2 or PGE (chronic infusion) • Adenosine infusions or boluses • Nitric oxide inhalation, nitrates (chronic infusion) • Calcium channel blockers Surgical options (in selected cases) • Heart–lung or single/double lung transplantation • 1.10.2 Atrial septostomy (only if no resting hypoxia) Venous thrombosis and pulmonary embolism The true incidence of pulmonary embolism (PE) is unknown but PE probably accounts for 1% of all admissions. Predisposing factors are discussed in Chapter 9, Haematology. One or more predisposing risk factors are found in 80–90% of cases. The oral contraceptive increases the risk of deep vein thrombosis (DVT)/PE two to four times. However, thromboembolism is rare in women taking oestrogens without other risk factors. Clinical features Nearly all patients have one or more of the following symptoms: dyspnoea, tachypnoea or pleuritic chest pain. With a large PE patients may present with collapse. Hypoxaemia may be present with moderate or large pulmonary emboli. Investigations • • • • • • • • Chest radiograph: may be normal; pleurally based, wedge-shaped defects described classically are rare and areas of oligaemia may be difficult to detect D-Dimer: will be raised in PE but the test is non-specific Helical CT scanning: will demonstrate pulmonary emboli in the large pulmonary arteries but may not show small peripheral emboli CTPA: the test of choice but really is to exclude major PE and subsegmental PE. True small peripheral PEs can be missed – and first generation scanners were only 70% sensitive compared to invasive pulmonary angiography ECG: may show sinus tachycardia and, in massive PE, features of acute right heart strain; nonspecific ST-segment and T-wave changes occur Arterial blood gases: show a low or normal PCO2 and may show a degree of hypoxaemia Ventilation/perfusion ( ) scanning: shows one or more areas of V/Q mismatching Pulmonary angiography: remains the ‘gold standard’, but this is underused In each case a clinical assessment of the probability of PE should be made. As demonstrated in the PIOPED study: Cases of high clinical probability combined with a high-probability scan are virtually diagnostic of PE Similarly, cases of low clinical suspicion combined with low-probability or normal V/Q scans • make the diagnosis of PE very unlikely • All other combinations of clinical probability and V/Q scan result should be investigated further • • Patients who present with collapse need urgent echocardiography, helical CT scan or pulmonary angiogram to demonstrate PE. Management In all cases of moderate or high clinical probability of PE, anticoagulation with heparin or lowmolecular heparin should be started immediately after baseline coagulation studies have been taken. If unfractionated heparin is used, the dose should be adjusted to maintain the activated partial thromboplastin time (APTT) to 1.5–2.5 times the control). Low-molecular-weight heparin has the advantage of once-daily subcutaneous injections that do not need monitoring. Warfarin should be started concurrently and heparin can be discontinued once the INR is 2–3. • • • • Warfarin is continued for 3–6 months in most cases; for PE occurring postoperatively, 6 weeks’ anticoagulation is adequate. In recurrent PE, anticoagulation should be for longer periods (eg 1 year) and consideration should be given to lifelong treatment In cases of collapse due to massive PE, thrombolysis with streptokinase or recombinant tPA given by peripheral vein should be considered. This should be avoided when the embolic material is an infected vegetation (eg intravenous drug abusers) Occasionally, pulmonary embolectomy is used for those with massive PE where thrombolysis is unsuccessful or contraindicated Inferior vena caval filters should be considered in patients in whom anticoagulation is contraindicated or in those who continue to embolise despite anticoagulation. 1.10.3 Systemic hypertension Overall, 30% of the UK adult population have hypertension, with the prevalence increasing with age to 70% in the eighth decade. Guidelines for treatment continually adapt to new clinical evidence, but the British Hypertension Society (BHS) has issued guidelines (Table 1.14) to identify those in need of treatment. Suggested treatment targets are <140/85 mmHg in general, and <130/80 mmHg for high-risk patients, such as patients with diabetes. A suggested treatment algorithm is given in Table 1.15. Other considerations in hypertension management • • • • Investigation of phaeochromocytomas: recommend three 24-h urinary catecholamine derivatives of all drugs on a vanilla-free diet (and off all drugs). Urinary metadrenalines may also be measured Hypertension increases the risk (Framingham data) of: stroke (37); cardiac failure (34); coronary artery disease (33); peripheral vascular disease (32) Potassium salt should be substituted for sodium salt where possible Drugs to avoid in pregnancy: diuretics, ACE inhibitors, angiotensin II receptor blockers. Drugs with well-identified risks preferred in pregnancy: β blockers (especially labetalol), methyldopa and hydralazine Young Black men have a poor response to ACE inhibitors and β blockers because they are salt • conservers by background, and so are resistant to renin manipulation and particularly likely to develop the side-effect of impotence. Table 1.14 British Hypertension Society Guidelines Systolic pressure (mmHg) Diastolic pressure Observation (mmHg) 180 160–179 110 100–109 Single reading Multiple readings 140–159 90–99 Multiple readings DM, TOD, 10year risk >20% 140–159 90–99 Multiple readings None of the above <140 <90 Multiple readings 130–139 80–85 Single reading >130 >0 Cofactor Recomm endation Treat Treat Treat Reas sess annually Reas sess annually Reas sess annually Reas sess in 5 years DM, diabetes mellitus; TOD, target organ damage (eg any cardiovascular disease, left ventricular hypertrophy by echocardiography or ECG, proteinuria). Table 1.15 Treatment algorithm for hypertension First line for those aged >55 years or Black patients First-line treatment for others Second-line treatment Third-line treatment Additional possibilities Calcium blocker or thiazide ACE inhibitor or ARB ACE inhibitor or ARB + calcium blocker or thiazide ACE Inhibitor or ARB + calcium blocker + thiazide Other diuretic, α/β blockers ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker. 1.10.4 Aortic dissection Two-thirds of tears occur in the ascending aorta with about a fifth occurring in the descending aorta. Mortality is highest in the first few hours if the dissection is untreated. The differential diagnosis for ascending dissection includes MI if the vulnerable right coronary ostium is involved (giving rise to an inferior infarct pattern). This is particularly important when considering thrombolysis; aortic regurgitation provides supportive evidence of the diagnosis. Associations with aortic dissection • • • • • • • • • • Systemic hypertension (present in 80%) Marfan’s syndrome Cystic medial degeneration (rare in the absence of Marfan’s syndrome) Noonan’s and Turner’s syndromes Trauma Aortic coarctation Congenital bicuspid aortic valve (present in 10–15% and dissection is therefore associated with aortic stenosis) Giant-cell arteritis Pregnancy (particularly in patients with Marfan’s syndrome) Cocaine abuse Involvement of ascending aorta may cause • • • • • Aortic regurgitation Inferior MI Pericardial effusion (including cardiac tamponade) Carotid dissection Absent or decreased subclavian pulse Medical therapy to be considered for • Old, stable dissections (>2 weeks) • Uncomplicated dissection of descending aorta • Isolated arch dissections Investigations for aortic dissection • • • • TOE, aortic MRI and contrast-enhanced spiral CT all have a high diagnostic sensitivity, but CT rarely identifies the site of the tear or the presence of aortic regurgitation or coronary involvement MRI is of the highest quality but is contraindicated in patients with pacemakers and certain vascular clips TOE is probably the most widely used investigation because it is available in the acute situation and has high sensitivity and specificity Aortography is no longer the gold standard and coronary angiography is applicable only when deciding on the need for concomitant CABG. Management of aortic dissection • • • • • Suspected aortic dissection is a medical and surgical emergency and requires prompt response, with mortality increasing by 1% for every hour. Long delays for diagnosis should be minimised. Untreated proximal dissection are almost always fatal. Descending aortic dissections have a better prognosis with 85% surviving their hospital stay but can still cause significant mortality if shock, organ ischaemia and renal failure occurs. Medical therapy with intravenous agents to reduce the blood pressure may help prevent extension of the dissection flap. Medical therapy remains the first-line therapy for Type B dissections (descending aorta only), with subsequent treatment based upon the clinical course. The mainstay of treatment of proximal dissections (Type A) is urgent surgery and even if successful, mortality can be as high as 20% at 2 weeks from complications of the dissection, including aortic rupture, stroke, visceral ischaemia, cardiac tamponade and circulatory failure. The aim of the surgery is to resect the region of intimal tear to prevent aortic rupture and cardiac tamponade. If the tear is extensive, partial or total aortic arch replacement may be required. The aortic valve may be suitable to be resuspended or may require replacement. Medical hypothermia is used but has not significantly improved post-operative mortality. Endovascular stent-graft placement has no role in Type A dissections but may help in Type B dissections when key aortic branches are compromised. APPENDIX I Normal cardiac physiological values ECG • • • • PR interval 0.12–0.20 s QRS duration >0.10 s QTc (males) 380 ms, (females) 420 ms QRS axis −308 to +908. Indices of cardiac function • Cardiac index = Cardiac output/body surface area (BSA) = 2.5–4.0 L/min per m2 • Stroke volume index = stroke volume/BSA = 40–70 mL/m2 5 • Systemic vascular resistance (SVR) = 80 × (Ao − RA)/cardiac output = 770–1500 dyn s/cm , where Ao is the mean aortic pressure and RA the mean right atrial pressure • Ejection fraction = Proportion of blood ejected from left ventricle = 50–70%. Cardiac catheterisation pressures mmHg Criteria for significant oxygen saturation setup Mean right atrial Right ventricular systolic 0–8 15–30 SVC/IVC to RA RA to RV >7% (eg ASD) >5% (eg VSD) End-diastolic 0–8 Pulmonary artery systolic 15–30 End-diastolic 3–12 Mean Pulmonary artery wedge A V Left atrial mean Left ventricular systolic End-diastolic Aortic systolic End-diastolic Mean 9–16 RV to PA Any level: SVC to PA Usual saturations (SaO2) Venous Arterial >5% (eg PDA) >7% 65–75% 96–98% 3–15 3–12 1–10 100–140 3–12 100–140 60–90 70–105 APPENDIX II Summary of further trials in cardiology Major trials Condition Heart failure Heart failure Heart failure Intervention β blockers ACE inhibitors Trials Main finding β blockers reduce MERIT-HF, CIBIS mortality and II, COPERNICUS morbidity SOLVD, ATLAS, CONCENSUS References Lancet 1999;353:2 001–7, Lancet 199 9;353:9–13, N Engl J Med 2001; 344:1659–67 N Engl J Med 199 ACE inhibitors 1;325:293–302, reduce mortality and Circulation morbidity 1999;100: 2312– 18 Cardiac resynchro MUSTIC, CRT reduces nisation therapy MIRACL, COMPA mortality and (CRT) NION, CARE-HF morbidity N Engl J Med 200 1;344:873–80, N Engl J Med 2002; 346:1845–53, N Engl J Med 2004; 350:2140–50, N Engl J Med 2005;352:1539–49 Ventricular arrhy Implantable defibri AVID, MADIT II, thmia llators (ICD) COMPANION N Engl J Med ICD reduce mortality 1997;337:1576– in primary and 83, N Engl J Med secondary 2002;346:877–83, prevention N Engl J Med 2004;350:2140–50 Acute MI Aspirin reduces mortality Lancet 1988;ii:349–60 Thrombolysis reduces mortality Lancet 1988;ii:349–60, Lancet 1992;339:7 53–70, New Engl J Med 1993;329:673 –82, Lancet 1986;i:397–401 ISIS, BHAT, CAP β blockers reduce RICORN mortality Lancet 1986;ii:57– 66, JAMA 1982;24 7:1707–14, Lancet 2001;357:1385–90 ACE inhibitors AIRE, SAVE, GISSI 3, TRACE Lancet 1993;342:8 21–8, N Engl J Med 1992;327:669 –77, Lancet 1994; 343:1115–22, N Engl J Med 1995;333:1670–6 Statins Lancet 1994;344:1 Statins are effective 383–89, N Engl J SSSS, WOSCOPS, in primary and Med 1995;333:130 HPS secondary 1–7, Lancet prevention 2002;360:7–22 Acute MI Ischaemic heart disease Ischaemic heart disease Ischaemic heart disease Aspirin Thrombolysis β blockers ISIS 2 ISIS 2, ISIS 3, GUSTO, GISSI 1 ACE inhibitors reduce mortality Chapter 2 Clinical Pharmacology, Toxicology and Poisoning CONTENTS 2.1 Clinical pharmacology terms 2.1.1 Pharmacokinetic terms 2.1.2 Pharmacodynamic terms 2.2 Drug metabolism and interactions 2.2.1 Genetic variations in drug metabolism 2.2.2 Liver enzyme induction 2.2.3 Liver enzyme inhibition 2.2.4 Failure of the combined oral contraceptive pill 2.3 Prescribing in special situations 2.3.1 Pregnancy and drug therapies 2.3.2 Drugs and breastfeeding 2.3.3 Liver disease 2.3.4 Renal failure 2.4 Selected drugs used in specific clinical conditions 2.4.1 Cardiology 2.4.2 Endocrinology 2.4.3 Gastroenterology 2.4.4 Neurology 2.4.5 Psychiatry 2.4.6 Rheumatology 2.4.7 Respiratory 2.4.8 Miscellaneous 2.5 Specific adverse effects 2.5.1 Secondary amenorrhoea 2.5.2 Bronchospasm 2.5.3 Dyskinesia and dystonia 2.5.4 Gynaecomastia 2.5.5 Hypothyroidism 2.5.6 Drug-induced liver injury 2.5.7 Drugs provoking myasthenia 2.5.8 Photosensitivity 2.5.9 Drug-induced vasculitis 2.5.10 Acute pancreatitis 2.5.11 Syndrome of inappropriate ADH secretion 2.5.12 Drug-induced diabetes insipidus 2.6 Poisoning 2.6.1 Paracetamol overdose 2.6.2 Tricyclic antidepressant and venlafaxine overdose 2.6.3 Theophylline toxicity 2.6.4 Carbon monoxide poisoning 2.6.5 Quinine toxicity 2.6.6 Iron poisoning 2.6.7 Salicylate overdose 2.6.8 Ethylene glycol poisoning 2.6.9 Haemodialysis for overdose or poisoning Clinical Pharmacology, Toxicology and Poisoning 2.1 CLINICAL PHARMACOLOGY TERMS 2.1.1 Pharmacokinetic terms Half-life (t ) is the time taken for plasma drug concentrations to fall by half, ie after 1 × t = 50%, 2 × t = 25%, 3 × t = 12.5%, etc. Volume of distribution (Vd) is a theoretical volume that describes the extent to which a drug is retained within the circulation or distributed elsewhere, eg a drug with a Vd of 5 L is mostly confined to the circulating compartment, a drug with Vd of 30 L is distributed within the extracellular compartment, and a drug with a Vd of 3000 L is highly distributed to extravascular tissues. 2.1.2 Pharmacodynamic terms Efficacy (E) is a measure of drug effects on a particular system, including maximal effect (Emax). A partial agonist (eg buprenorphine) has a lower Emax than a full agonist (eg morphine) and cannot elicit a full response even if the dose is increased. Potency expresses drug efficacy with respect to drug concentrations or dose, and is less clinically relevant than efficacy, eg if atorvastatin 10 mg may lower cholesterol to the same extent as simvastatin 40 mg, then the former has a fourfold higher potency. 2.2 DRUG METABOLISM AND INTERACTIONS 2.2.1 Genetic variations in drug metabolism Genetic variation may alter response to drug therapy, eg angiotensin-converting enzyme (ACE) inhibitors prevent the occurrence of diabetes in homozygous carriers of the 1166A variant of the angiotensin type 1 receptor gene, but not in heterozygotes and non-carriers. Polymorphisms affecting tumour necrosis factor promoter regions may predict the response to infliximab in patients with rheumatoid arthritis. Drug acetylation occurs within the liver and to a lesser extent within the bowel, kidney and other tissues. It is subject to genetic variation, and about 50% of all White individuals are rapid or slow acetylators. Rapid acetylator phenotype is associated with lower drug concentrations and diminished therapeutic effects, whereas metabolite concentrations are higher, eg rapid acetylator phenotype may make isoniazid less effective against tuberculosis and confer a higher risk of hepatitis from its metabolite. Conversely, slow acetylator phenotype may be associated with a higher risk of peripheral neuropathy as a direct toxic effect of isoniazid. Other genetic variations in drug metabolism include: Nateglinide is metabolised more slowly by patients with the CYP2C9*3/*3 genotype than by carriers of CYP2C9*1, so that the former patients may be at increased risk of hypoglycaemia • s-Mephenytoin: 3–5% of the UK population are poor metabolisers of this antiepileptic agent. • Drug-induced lupus is associated with slow acetylation and possession of HLA-DR4. In contrast to autoimmune systemic lupus erythematosus (SLE), the incidence is equal in men and women, and laboratory findings include antibodies to histones and single-stranded DNA. Clinical features of drug-induced lupus include: • arthralgia • butterfly rash • pleurisy. Renal involvement is uncommon (apart from hydralazine), and neuropsychiatric manifestations are unusual. Drugs causing a lupus erythematosus-like syndrome • • • • • • • • • • • • • • • β Blockers Hydralazine Phenytoin Chlorpromazine Isoniazid Procainamide Clonidine Lithium Sulfasalazine Flecainide Methyldopa Sulfonamides Haloperidol Penicillin Tetracyclines 2.2.2 Liver enzyme induction Many drugs are capable of inducing liver enzyme systems, thereby increasing the metabolism (and decreasing the effectiveness) of other drugs. Enzyme induction normally takes several days to occur due to the time required to synthesise new enzyme. Enzyme induction may decrease the effectiveness of: • • • • hydrocortisone oral contraceptive pill phenytoin warfarin. Some drugs that cause this effect can be remembered by the mnemonic PC BRAS: Phenytoin Carbamazepine Barbiturates Rifampicin Alcohol (chronic excess) St John’s wort 2.2.3 Liver enzyme inhibition A number of drugs are capable of inhibiting hepatic enzyme systems, and the effect may be immediate. Enzyme inhibition can slow the metabolism of other drugs, thereby increasing their plasma concentrations and the risk of adverse effects. Enzyme inhibition can increase the effects of: • • • • • • carbamazepine ciclosporin phenytoin statins theophylline warfarin. Drugs capable of inhibiting liver cytochrome P450 enzymes often exert their therapeutic effects via enzyme inhibition too. Some examples may be recalled by the mnemonic AODEVICCES: Allopurinol (xanthine oxidase inhibitor) Omeprazole (proton pump inhibitor) Disulfiram (aldehyde dehydrogenase inhibitor) Erythromycin Valproate (GABA [γ-aminobutyric acid] transaminase inhibitor) Isoniazid (nucleic acid synthetase inhibitor) and Itiaconazole/fluconazole (inhibit enzymes in ergosterol synthesis) Ciprofloxacin Cimetidine Ethanol: acute intoxication Sulfonamide (dihydropteroate synthase inhibitor) 2.2.4 Failure of the combined oral contraceptive pill Any condition that leads to impaired absorption of the components of the contraceptive pill (eg travellers’ diarrhoea) can result in its failure as a contraceptive agent. In addition: The oestrogen component may be metabolised more rapidly in the presence of liver enzyme induction (see Section 2.2.2), leading to pill failure Pill failure may also result from concomitant broad-spectrum antibiotic usage, eg penicillins, • cephalosporins, quinolones or tetracyclines may eradicate gut flora that deconjugate bile salts, thereby interrupting enterohepatic cycling and reducing oestrogen reabsorption • 2.3 PRESCRIBING IN SPECIAL SITUATIONS 2.3.1 Pregnancy and drug therapies During the first 16 weeks of pregnancy, drugs may exert teratogenic effects resulting in fetal malformations and drug treatment is generally avoided if possible. Particular associations are as follows: • • • • • ACE inhibitors and angiotensin receptor blockers: oligohydramnios Lithium: cardiac abnormalities Phenytoin: facial fusion abnormalities such as cleft lip and palate Sodium valproate and retinoids: neural tube defects and spina bifida Warfarin: abnormalities of long bones and cartilage. Later in pregnancy, certain drugs may cross the placenta and cause harm to the fetus: • Carbimazole: neonatal goitre (which may even be large enough to obstruct labour) • Gentamicin: cranial nerve VIII deafness in the newborn. 2.3.2 Drugs and breastfeeding Infants under 1 month of age are highly susceptible to the effects of drugs in breast milk due to immature mechanisms of metabolism and excretion. Drugs that may be excreted in breast milk and are recognised as causing toxicity include the following: • • • • • • Amiodarone: thyroid anomalies Cytotoxics and chloramphenicol: blood dyscrasia Gold: haematological reactions and kidney injury Indometacin: neonatal seizures Iodides: thyroid disturbance Lithium: involuntary movements • Oestrogens: feminisation of male infants. 2.3.3 Liver disease Patients with liver impairment are more susceptible to sedative effects of drugs, and certain drugs may provoke hepatic encephalopathy, eg opioids and benzodiazepines. Thiazides and loop diuretics may worsen hypokalaemia and cause acute encephalopathy. The presence of liver disease may have important effects on drug pharmacokinetics and alter their clinical effects: Drugs excreted via the bile, such as rifampicin, may accumulate in patients with obstructive jaundice Hypoalbuminaemia reduces the extent of drug protein binding so that there is an increased • proportion of ‘free’ unbound drug, and increased risk of drug toxicity, eg phenytoin • Reduced clotting factor synthesis may enhance the risk of bleeding associated with warfarin Salt and water retention and ascites may be worsened by non-steroidal anti-inflammatory drugs • (NSAIDs) and corticosteroids. • 2.3.4 Renal failure In patients with established renal impairment, nephrotoxic agents may exacerbate renal damage (especially in acute renal failure). Patients with low glomerular filtration rate (GFR) will be prone to accumulation of drugs normally eliminated by the kidney, eg water-soluble drugs. The following drugs that may cause toxicity due to accumulation in patients with severe renal failure (GFR < 10 mL/min) include: • • • • • • • • Atenolol: bradycardia, heart block Digoxin: cardiac arrhythmias, heart block Enoxaparin: bleeding risk Erythromycin: encephalopathy Lithium: cardiac arrhythmias and seizures Penicillins (high dose): lead to encephalopathy Cephalosporins (high dose): encephalopathy Trimethoprim: hyperkalaemia. Nephrotoxic drugs capable of precipitating or worsening acute renal impairment should be avoided where possible. Therapeutic drug monitoring may be required in some cases, eg intravenous gentamicin and vancomycin. The following are examples of nephrotoxic drugs: • • • • • ACE inhibitors and angiotensin receptor antagonists Aminoglycosides Amphotericin Cytotoxics eg cisplatin Diuretics (especially high doses of loop diuretics) • NSAIDs including high-dose aspirin • Calcineurin inhibitors (ciclosporin and tacrolimus). Other drugs may have specific nephrotoxic effects, such as gold-induced proteinuria or nephrotic syndrome, which is usually due to membranous glomerulonephritis. (See also Chapter 15, Nephrology.) 2.4 SELECTED DRUGS USED IN SPECIFIC CLINICAL CONDITIONS 2.4.1 Cardiology Abciximab (ReoPro) This chimaeric monoclonal antibody irreversibly binds GPIIb/IIIa glycoprotein receptors, preventing the final common pathway of platelet activation and aggregation. It is capable of preventing acute thrombosis and restenosis in patients with unstable angina who are undergoing coronary artery stent insertion. Risks of thrombocytopenic haemorrhage may be reversed by platelet administration. Abciximab should be used only once, due to concerns about efficacy and adverse effects, although emerging data suggest that repeated administration might be safe and efficacious. Adenosine Adenosine is a purine nucleoside with a half-life of 8–10 seconds. It acts via adenosine receptors that activate K+ channels in sino-atrial and atrioventricular nodes. It is capable of terminating supraventricular tachycardia (SVT), and is used as a diagnostic aid to distinguish SVT from ventricular tachycardia. Its duration of action may be significantly increased by dipyridamole. Side-effects of adenosine • • • • Anxiety Chest tightening Bronchospasm (avoid in asthmatic patients) Facial flushing Aliskiren Aliskiren is a direct renin inhibitor (inhibits conversion of angiotensinogen to angiotensin I). It is licensed for treatment of essential hypertension, and is effective alone or in combination with other antihypertensives (including optimal doses of ACE inhibitor or angiotensin receptor antagonist). Adverse effects include renal impairment and hyperkalaemia, especially in patients receiving other medications capable of increasing serum potassium (eg spironolactone, ACE inhibitor, angiotensin receptor antagonists). Amiodarone Amiodarone may be used to control supraventricular and ventricular arrhythmias. Its main action is to prolong the refractory period, with corresponding QT prolongation on the ECG. It reduces mortality in patients with recurrent ventricular tachycardia (VT) or hypertrophic cardiomyopathy. • • • • • • It is iodine-containing and has a very long half-life (26–127 days), hence its effects may persist for a long time after discontinuation Protein-binding interaction causes increased effects of digoxin and warfarin Given intravenously, the antiarrhythmic action occurs within a few hours; given orally this may take 1–3 weeks, usually a loading dose being given Amiodarone is the least negatively inotropic antiarrhythmic, with the exception of digoxin, however, a rapid bolus of amiodarone can still reduce blood pressure significantly Hypothyroidism may arise from increased production of reverse triiodothyronine (T3) in the liver Hyperthyroidism may result from enhanced peripheral deiodination of thyroxine (T4) to T3 Side-effects of amiodarone • • • • • • • • • • • • Arrhythmias (torsades de pointes) Ataxia Alveolitis Hepatitis Hyperthyroidism Hypothyroidism Metallic taste Peripheral neuropathy Photosensitivity Pulmonary fibrosis Reversible corneal microdeposits Slate-grey discoloration of skin Angiotensin-converting enzyme inhibitors ACE inhibitors reduce mortality in heart failure, prolong survival after myocardial infarction and slow progression of diabetic nephropathy. They are contraindicated in bilateral functional renal artery stenosis and should be used with caution in severe renal impairment. Dry cough occurs in 10–20%, thought to be due to increased alveolar and bronchiolar concentrations of kinins • Hypersensitivity reactions can occur, including angio-oedema • Potassium may increase due to inhibition of aldosterone effects. • Angiotensin-receptor blockers Angiotensin II receptor (type AT1) antagonists do not inhibit bradykinin breakdown (unlike ACE inhibitors). Cough is a recognised adverse effect but it is less common than after ACE inhibitors. There is improved survival in hypertension, cardiac failure and myocardial infarction. Angiotensin receptor blockers (ARBs) also delay progression of diabetic nephropathy (see Nephrology, Chapter 15). They may precipitate acute renal failure in patients with reduced renal blood flow (eg bilateral renal artery stenosis, severe cardiac failure, hypovolaemia) in an identical manner to that seen with ACE inhibitors. Angio-oedema is a recognised complication. Clopidogrel Clopidogrel is a prodrug that exerts antiplatelet effects via irreversible binding to the P2Y12 receptor on the platelet surface, thereby blocking ADP binding and preventing glycoprotein GPIIb/IIIa activation. The duration of the antiplatelet effects is longer than with aspirin, and the bleeding risk may remain increased for up to 7 days after drug cessation. Clopidogrel may be used as monotherapy in patients who cannot tolerate aspirin, or in combination with aspirin to treat acute coronary syndrome, for up to 12 months, then reverting to aspirin alone. Neutropenia is a rare but recognised adverse effect. Digoxin Digoxin delays atrioventricular node conduction, and may slow ventricular rate in atrial fibrillation and flutter. It has a limited role as a positive inotrope but may be effective in patients with coexistent heart failure and atrial fibrillation. Eight-five per cent is eliminated unchanged in the urine; digoxin may accumulate in renal impairment • The steroid-like structure of digoxin has occasionally caused gynaecomastia with chronic use • Digoxin has a narrow therapeutic index, and small increases in dose may cause toxicity. • Digoxin toxicity Any arrhythmia may occur with digoxin toxicity, including heart block and atrial arrhythmias. Toxicity often causes severe bradycardia and hypotension, and may be accompanied by hyperkalaemia. The ‘reversed tick’ (ST-segment depression in the inferior and lateral leads on the ECG) may occur with digoxin therapy and does not necessarily indicate toxicity Electrolyte imbalance may predispose to digoxin toxicity: hypokalaemia, hypomagnesaemia and • hypercalcaemia Amiodarone may displace digoxin from tissue-binding sites, leading to toxicity. Quinine and • calcium antagonists may impair renal tubular clearance of digoxin and cause toxicity. • Toxic effects of digoxin • Anorexia • • • • • Nausea/vomiting Arrhythmias (eg ventricular tachycardia, heart block) Severe hypotension Yellow vision (xanthopsia) Diarrhoea Flecainide This is a class 1c agent used for treatment of ventricular arrhythmias and pre-excitation syndromes, and for chemical cardioversion of acute atrial arrhythmias. The CAST trial suggests that flecainide is pro-arrhythmic after a myocardial infarction and it is normally avoided in patients with ischaemic heart disease or left ventricular impairment. Its half-life is about 16 hours; other adverse effects are vertigo and visual disturbance. HMG-CoA reductase inhibitors Statins inhibit the rate-limiting enzyme in cholesterol synthesis (3-hydroxy-3-methyl-glutaryl coenzyme A [HMG-CoA] reductase), which is normally most active during sleep (due to fasting and increased hepatic blood flow). Statins cause upregulation of low-density lipoprotein (LDL) receptors, thereby reducing LDL by 30%, and increase high-density lipoprotein (HDL). Some statins may cause a modest decrease in triglyceride concentrations; Atrovastatin has been associated with reduction in triglyceride levels, there is only limited data to suggest this alters cardiovascular events. Statins reduce mortality in patients with ischemic heart disease, diabetes mellitus, hypertension or other major cardiovascular risk factors. Statins may cause rhabdomyolysis and 10–20% of patients discontinue treatment annually due to myopathy. This is more likely in patients with renal impairment, after high doses or if combined • with a fibrate; drug-induced hepatitis may also occur. Drug concentrations and the risk of adverse effects are increased for most statins when patients concomitantly receive an enzymeinhibiting drug, eg clarithromycin (see 2.2.3) In patients with established coronary heart disease, the Joint British Societies recommend a • target total serum cholesterol of ≤4 mmol/L and LDL cholesterol of ≤2 mmol/L. • Ivabradine Ivabradine acts on the If channel (an inward sodium-potassium channel) found predominantly in the sino-atrial node, resulting in reduced resting and exercising heart rate. It is indicated for the treatment of angina, and may be less negatively inotropic than β blockers and may cause fewer symptoms attributed to reduced peripheral blood flow (muscle cramps, cold peripheries). Although patients may report less angina and have improved exercise times in smaller studies, major trials have not shown improved outcomes for patients with angina. A signal of harm was noted in a subset of the SHIFT study which may require reassessment of the use of this drug for angina. It is contraindicated in patients with resting bradycardia and sick sinus syndrome, or if patients are taking a β blocker or rate-limiting calcium channel blocker (diltiazem, verapamil). Ivabradine is also licenced for the treatment of heart failure patients in whom the heart rate is not adequately controlled on beta- blockers. The SHIFT study suggested an improvement in heart failure related readmissions and death. Nicorandil A potassium channel opener that induces arterial vasodilatation, this also possesses a nitrate component that promotes venous relaxation. It is used as an antianginal agent. The side-effects are transient headache, flushing and dizziness. In large doses it may cause hypotension with a reflex tachycardia. Prasugrel and Ticagrelor Both drugs are new generation antiplatelets with greater antiplatelet potency than clopidogrel and a faster time to onset. Both are P2y12 receptor inhibitors and are used for acute coronary syndrome patients, particularly those undergoing coronary stenting. Both are associated with greater rates of bleeding complications. Tricagrelor is commonly associated with bradycardia on monitoring and the sensation of breathlessness which may lead to discontinuation. Thiazide diuretics Thiazides are capable of lowering blood pressure. The mechanism is uncertain, but is independent of the modest diuretic effect provided by these agents. Maximum blood pressure reduction is achieved using low doses (eg bendroflumethiazide 2.5 mg daily) with little additional BP lowering beyond this dose range. They are associated with a number of dose-dependent metabolic effects: • Hyponatraemia, hypokalaemia and hypomagnesaemia: a hypochloraemic alkalosis • Raised plasma urate due to reduced tubular clearance; gout may be precipitated Diabetic glycaemic control may worsen on thiazides due to impaired insulin release and • increased insulin resistance • Postural hypotension, photosensitivity and impotence (mechanism unclear). Rare dose-independent side-effects of thiazide diuretics • Agranulocytosis • Pancreatitis • Thrombocytopenia Novel anticoagulant agents Dabigatran is a direct inhibitor of free and fibrin-bound thrombin, and of thrombin-induced platelet aggregation. Apixaban and rivaroxaban are direct inhibitors of activated factor X. These novel oral anticoagulants are licensed for prevention of venous thromboembolism after elective hip or knee replacement, and stroke prevention in non-valvular atrial fibrillation. Rivaroxaban is also licensed for treatment and prevention of deep vein thrombosis and pulmonary embolus. There is no specific antidote available for these anticoagulants, and they are contraindicated in patients at high risk of haemorrhage, including gastrointestinal ulcer or malignancy, recent surgery, recent intracranial haemorrhage, or suspected oesophageal varices or vascular abnormalities. They should not be administered at the same time as other anticoagulation therapy, including low-molecular-weight heparin. 2.4.2 Endocrinology Carbimazole Carbimazole inhibits a peroxidase enzyme that catalyses several steps in the conversion of tyrosine to thyroid hormone. It takes at least 6 weeks to reduce blood levels of thyroid hormones. Therefore, somatic symptoms of hyperthyroidism, such as tachycardia and anxiety, require control by β blockers (eg propranolol). Agranulocytosis may occur within the first 16 weeks of therapy and in the event of sore throat, patients should be advised to seek medical help • The drug crosses the placenta, and may cause neonatal goitre and hypothyroidism. • Exenatide This is a synthetic form of exendin-4 that potentiates the release of insulin in response to hyperglycaemia. It is licensed for use in patients with type 2 diabetes in combination with metformin or sulfonylurea or both, and in patients with inadequate glycaemic control. It requires subcutaneous administration, and its adverse effects include dyspepsia and altered bowel habit. Hormone replacement therapy On average, over a third of a woman’s life is in the postmenopausal phase, yet only 12% of women receive hormone replacement therapy (HRT); 60–75% experience vasomotor symptoms that may be reduced by HRT. Without HRT, women aged 70 years have a 50% reduction in bone mass and one in two will have an osteoporosis-related fracture HRT may reduce the occurrence of fractures. There is uncertainty over the possible impact of • HRT on heart disease and stroke risk, and HRT may be associated with an increased risk of breast cancer. (See also Chapter 4, Endocrinology, Section 4.3.6). • Nateglinide and repaglinide These agents have a short duration of action and may be used to stimulate insulin release in patients with type 2 diabetes before meals. Similar mechanism of action to sulphonylureas but much shorter duration of action and so can be taken before meals to control postprandial hyperglycaemia. They may also be given alongside metformin. Side-effects include gastrointestinal upset and hypersensitivity reactions. Acarbose Acarbose inhibits intestinal α-glucosidase and thereby delays absorption of starch and sucrose. It reduces postprandial hyperglycaemia in type 1 diabetes and is used as an adjunct to metformin or sulfonylurea therapy in type 2 diabetes. Excess flatus is a common adverse effect. Sitagliptin Sitagliptin is a dipeptidylpeptidase-4 (DPP-4) inhibitor that increases insulin secretion and inhibits glucagon secretion. Sitagliptin may be added to metformin or a thiazolidinedione (see below) if glycaemic control is inadequate. DPP-4 inhibitors depend on intrinsic insulin secretion and therefore are not expected to cause hypoglycaemia. 2.4.3 Gastroenterology Sulfasalazine Sulfasalazine consists of a sulfonamide molecule plus 5-ASA. It is used in the treatment of ulcerative colitis, and also as a disease-modifying anti-rheumatic in rheumatoid arthritis. The sulfonamide moiety frequently leads to gastrointestinal upset. Other key features are as follows: Oligospermia, leading to male infertility, may occur, but this is usually reversible on stopping sulfasalazine • Patients may note orange discoloration of body fluids Slow acetylators may experience more toxicity with sulfasalazine due to exposure to higher • levels of the sulfonamide constituent Rare adverse effects include Stevens–Johnson syndrome, blood dyscrasias (especially • agranulocytosis and aplasia) and the nephrotic syndrome. • Mesalazine and olsalazine Mesalazine and olsalazine differ from sulfasalazine in being purely 5-aminosalicylic acid (5-ASA) molecules that are split for local action in the colon. They suppress local inflammation in ulcerative colitis. They have some systemic side-effects, including nausea, abdominal pain, headache and sometimes worsening of colitis Rare side-effects of mesalazine and olsalazine include reversible pancreatitis, blood dyscrasias • and interstitial nephritis (with mesalazine). • Orlistat Orlistat inhibits the action of pancreatic lipase and may be used in obesity where the body mass index is >30 kg/m2 and a prerequisite of treatment is that the patient has been able to lose 2.5 kg in weight over a 4-week period. It causes liquid, oily stools and may reduce the absorption of fat-soluble vitamins. Probiotic therapy Probiotics have been proposed as a means of reducing the occurrence of antimicrobial-associated diarrhoea; however, a large recent study (PLACIDE) found that daily administration of a mixed preparation of lactobacilli and bifidobacteria for 21 days had no effect on the occurrence of antibiotic-associated diarrhoea or Clostridium difficile gastroenteritis in patients aged ≥65 years. 2.4.4 Neurology Treatment of Parkinson’s disease Enhanced dopaminergic transmission is central to the medical management of Parkinson’s disease: • • • • Selegiline is a type B monoamine oxidase inhibitor (MAO-B); inhibition of monoamine oxidase potentiates dopamine and reduces end-dose akinesia. It was thought that selegiline might also retard progression of Parkinson’s disease by preserving dopaminergic neurons. This is now known to be untrue Amantadine potentiates dopamine by preventing its reuptake into presynaptic terminals Levodopa (L-dopa) is absorbed in the proximal small bowel by active transport, but the presence of amino acids (and thus meals) may reduce absorption. It is a prodrug that must be converted to dopamine within the nigrostriatal pathway. The drug is largely metabolised by catechol-Omethyltransferase. After 8 years of therapy with L-dopa, 50% of patients will have choreoathetoid dyskinesia and end-dose akinesia. By this time many patients will have deteriorated to pretreatment levels of disability due to progression of Parkinson’s disease Dopamine receptor agonists include apomorphine, bromocriptine, cabergoline, pergolide, pramipexole and ropinirole. These agents cause less dyskinesia than L-dopa but they are associated with more neuropsychiatric adverse effects. Certain of these agents have been associated with pulmonary and retroperitoneal fibrosis (bromocriptine, cabergoline and pergolide). Apomorphine is a powerful dopamine agonist which needs to be given by parenteral administration under specialist supervision. It is highly emetogenic and domperidone must therefore be given 2 days before the start of therapy. Side-effects of L-dopa • • • • • • Cardiac arrhythmias Involuntary movements (dyskinesia) occur commonly; seizures are rare Nausea and vomiting Postural hypotension Psychosis (depression or mania) Somnolescence (including sudden onset) Treatment of epilepsy Recent developments in the therapeutics of epilepsy have concentrated on agents that interact with neurotransmitters: Lamotrigine inhibits the excitatory effects of glutamate within the central nervous system (CNS). Used to treat partial or generalized seizures, absence seizures, Lennox-Gastaut syndrome and • bipolar disorder. Adverse effects include mood changes, maculopapular rashes, influenza-like symptoms and Stevens–Johnson syndrome. It has no significant effect on hepatic cytochrome P450 enzyme activity • • • • • • Gabapentin is a pentameric isomer of γ-aminobutyric acid (GABA), an inhibitory CNS neurotransmitter. It is used to treat partial seizures with or without secondary generalization, and neuropathic pain. Leviracetam binds to SV2A, a synaptic vesicle protein, and modulates the release of various CNS neurotransmitters, including increased GABA release. It is used in combination with other antiepileptic drugs for the treatment of partial or generalised seizures and myoclonic jerks Vigabatrin irreversibly inhibits GABA transaminase, so that GABA activity is enhanced. Used to treat partial complex seizures or secondary generalization, infantile spasms and other resistant seizure types. Adverse effects include mood disturbance and psychosis in 5%. Severe visual field defects may occur from 1 month to several years after initiation, so regular visual field assessment is advised Benzodiazepines (eg clonazepam, lorazepam) act at a specific receptor site linked to the GABA receptor to cause increased binding affinity between GABA and its receptor Carbamazepine is a derivative of the tricyclic antidepressants and is useful for epilepsy and also neural pain (eg trigeminal or postherpetic neuralgia). Patients commonly experience headaches and diplopia soon after initiation of carbamazepine, and 5–15% of patients develop a generalised morbilliform rash. More serious dermal complications have been reported, including toxic epidermal necrolysis Sodium valproate may be used in generalised epilepsy, absence attacks and temporal lobe epilepsy. It inhibits liver enzymes and thereby increases drug concentrations and toxicity of other antiepileptics such as phenytoin. It may cause alopecia, with curly regrowth after stopping the drug, and causes hyperammonaemia; ammonia concentrations can be used to monitor valproate toxicity. Adverse effects of valproate • • • • • • • • Alopecia Hepatitis (sometimes fatal) Amenorrhoea Liver enzyme inhibition Ataxia Thrombocytopenia Gynaecomastia Weight gain 5-Hydroxytryptamine agonists (sumatriptan and rizatriptan) 5-Hydroxytryptamine (5HT) agonists are used during the acute phase of migraine. They maintain vascular tone and prevent headache associated with the vasodilator phase of migraine. They must not be given in hemiplegic migraine, or within 24 hours of ergotamine, because intense vasospasm may lead to permanent neurological damage. Sumatriptan may lead to permanent neurological damage. It may also cause angina due to coronary vasospasm. For this reason it is now rarely used. Side-effects of sumatriptan • • • • • Chest pain Flushing Drowsiness Vasospasm Fatigue 2.4.5 Psychiatry Chlorpromazine Chlorpromazine blocks many different receptors, it acts as a dopamine blocker, an α blocker, an anticholinergic and an antihistamine. It may cause QT prolongation on the ECG, particularly when used in high doses. Adverse effects of chlorpromazine • • • • • • • Agranulocytosis Contact dermatitis and purple pigmentation of the skin Dystonias (including oculogyric crisis) Neuroleptic malignant syndrome Photosensitivity Tardive dyskinesia (chronic use) Ventricular tachycardia (prolonged QT) Other antipsychotics Newer, so-called ‘atypical’ antipsychotic agents have a different adverse effect profile, and generally cause less sedation. Olanzapine and risperidone are associated with an increased risk of stroke in elderly patients, and should be used only with caution in this group. Lithium Lithium carbonate is used for prophylaxis in bipolar affective disorder, acute mania/hypomania and aggressive behaviour in patients with learning disabilities. It has a narrow therapeutic range (0.5–1.0 mmol/L). Toxic effects occur at levels >2.0 mmol/L. • • • • • Toxicity is more likely in renal impairment or when there are imbalances of electrolytes, or if lithium excretion is impaired by diuretics, ACE inhibitors or NSAIDs Lithium may cause histological changes in the kidney, and it has been recommended that longterm treatment is reviewed every 2–3 years Polyuria arises due to nephrogenic diabetes insipidus; lithium prevents antidiuretic hormone (ADH) from interacting with the collecting duct receptor, so leading to water loss. There is a compensatory increase in ADH release. Lithium is thought to downregulate expression of Aquaporin2, thereby decreasing sensitivity to ADH in the collecting ducts. Antacids, theophylline and acetazolamide lead to decreased plasma lithium carbonate CNS toxicity has been described with selective serotonin reuptake inhibitors (SSRIs), carbamazepine and phenytoin, methyldopa, antipsychotics (especially haloperidol), calcium channel blockers and sumatriptan. Toxic effects of lithium • At 1–2 mmol/L • Anorexia and vomiting • Ataxia and dysarthria • Blurred vision • Coarse tremor • Diarrhoea • Drowsiness • Muscle weakness • Severe toxicity >2 mmol/L • Circulatory failure • Coma • Convulsions • Death • Hyperreflexia • Oliguria • Toxic psychoses Side-effects of lithiuma • Common • Fine tremor (in about 15% of patients) • Leukocytosis • Loose motions • Nausea • Oedema • Polydipsia • Polyuria • Weight gain • Rare • Goitre • Hypothyroidism • Interstitial nephritis • Worsening of psoriasis and acne aMay arise despite therapeutic range dosing. Citalopram and escitalopram Recent data have shown that citalopram and its S-enantiomer escitalopram may cause dose-dependent prolongation of the QT interval on the ECG, raising concerns about the possibility of potentially fatal arrhythmias, including torsades de pointes. Citalopram and escitalopram should not be used in patients with congenital long QT syndrome or preexisting QT interval prolongation, or combined with other medicines that prolong the QT interval. An ECG should be performed before starting treatment in patients with cardiac disease or electrolyte disturbances. The maximum citalopram daily dose is 40 mg in adults and 20 mg for those aged >65 years or with liver disease. The maximum dose of escitalopram is 20 mg and 10 mg in those aged >65 years. 2.4.6 Rheumatology Methotrexate Methotrexate is a folate antagonist (blocking dihydrofolate reductase) that is widely used as an immunosuppressant in autoimmune rheumatic diseases. It is the first line Disease Modifying AntiRheumatic Agent (DMARD) in rheumatoid arthritis, but it’s use is common in many of the other rheumatic diseases (eg vasculitis, lupus). Methotrexate is administered once weekly, either as an oral tablet or as a subcutaneous injection. Awareness of weekly dosing is important, as inadvertent prescribing daily may result in severe toxicity, including mucositis, bone marrow suppression and pancytopenia. Treatment is to provide the active metabolite of folic acid: IV folinic acid. Methotrexate toxicity may occur when a patient is inadvertently prescribed a second folate antagonist, for example trimethoprim (this combination is hazardous and must be avoided. In standard doses of methotrexate, there are several common side effects that are encountered: • Nausea • Hepatitis • Pneumonitis • Bone marrow suppression Therefore all patients on methotrexate should have regular monitoring, including monthly blood tests. Methotrexate is also an abortive agent and a 3-month washout is needed prior to conception; patients prescribed the drug must have appropriate pregnancy counselling. Agents used in the treatment of gout Allopurinol inhibits xanthine oxidase, the enzyme that converts purines into uric acid, and so prevents gout. However, commencement of therapy will occasionally provoke an acute attack of gout. Established gouty tophi may regress with chronic use of allopurinol. Azathioprine, a prodrug, is converted to 6-mercaptopurine in the body and may accumulate, causing bone marrow toxicity in patients receiving allopurinol The renal clearance of cyclophosphamide may also be impeded in patients receiving allopurinol, • and this again leads to marrow toxicity. • Colchicine inhibits macrophage migration into a gouty joint but its use is limited by the frequent occurrence of diarrhoea. It has therefore been said that with colchicine ‘you run before you can walk!’. Urate oxidase enzymatically degrades urate to allantoin. Intravenous administration causes a significant reduction in serum urate concentrations (by up to 95%) and is used to prevent renal impairment in tumour lysis syndrome. Febuxostat Febuxostat is a novel xanthine oxidase inhibitor. It inhibits the formation of urate and over a sufficient period will lower total body urate and minimize the risk of gout. It is generally reserved for patients intolerant of allopurinol. 2.4.7 Respiratory Leukotriene antagonists Agents such as montelukast block the effects of leukotriene in the airways. They are used as adjunctive therapy in mild-to-moderate asthma, particularly with an allergic component, but they are ineffective in the setting of acute asthma. Churg–Strauss-like eosinophilic vasculitis and peripheral neuropathy have been reported with these agents. Omalizumab Omalizumab is a monoclonal antibody that binds to immunoglobulin E (IgE), and is licensed for use in the prophylaxis of severe allergic asthma confirmed by allergy testing. It requires subcutaneous administration, and adverse effects include hypersensitivity reactions and the Churg–Strauss syndrome. Tiotropium Tiotropium is an M3-selective muscarinic receptor antagonist that alleviates bronchospasm and minimises respiratory secretions. It has high receptor affinity, and its dissociation half-life is 27 hours, so that it is administered once daily. Adverse effects include dry mouth, tachycardia, dizziness, blurred vision, constipation and acute urinary retention. It should be used with caution in patients with narrow-angle glaucoma and bladder neck obstruction, or benign prostatic hyperplasia. 2.4.8 Miscellaneous A detailed description of the mechanism of action, important pharmacokinetics and characteristic or serious side-effects of commonly used antibacterial, antiviral and anthelmintic agents is provided in Chapter 11, Infectious Diseases and Tropical Medicine. Ciprofloxacin This 4-quinolone inhibits DNA bacterial gyrase, an enzyme that prevents supercoiling of bacterial DNA. It is active against both Gram-positive and Gram-negative organisms. It is a liver enzyme inhibitor and may increase the effect of theophylline in particular. Ciprofloxacin is not recommended for children aged <12 years (except in cystic fibrosis) because of the potential for causing bony anomalies. Adverse effects of ciprofloxacin • • • • • • • Anaphylaxis Impaired motor function Arthralgia Photosensitivity Crystalluria Sedation (which may affect driving) Diarrhoea Seizures – occur because ciprofloxacin can compete with the inhibitory neurotransmitter, GABA, • within the brain Ciclosporin A Ciclosporin A may be used to treat psoriasis and is used to reduce transplant rejection and it has significantly improved graft survival. After initiation of therapy (when doses are usually highest) it causes dose-dependent nephrotoxicity and has a narrow therapeutic range; therapeutic drug monitoring is indicated. Unfortunately, late nephrotoxic effects do occur and are often unrelated to plasma levels. (See also Chapter 15, Nephrology.) Gum hyperplasia is common; it is increased in individuals with poor oral hygiene, and also those concomitantly taking dihydropyridine calcium channel blockers. As with most immunosuppressants, there is an increased risk of skin and lymphoproliferative malignancy with long-term therapy. Adverse effects of ciclosporin • • • • • • • • • Burning hands and feet (especially during first week of therapy) Hypertension Hypertrichosis Fluid retention Liver dysfunction Gum hyperplasia Nephrotoxicity Hyperkalaemia Algodystrophy (complex regional pain syndrome) Cytotoxics Most cytotoxic agents have the potential to cause marrow suppression. Specific-side effects of cytotoxic agents • Bleomycin Causes dose-dependent lung fibrosis; it is one of the least myelotoxic chemotherapeutic • agents • Capecitabine • Desquamation (hand-foot syndrome) • Cisplatin May cause ototoxicity, nephrotoxicity (interstitial nephritis), hypomagnesaemia and • peripheral neuropathy • Doxorubicin May cause skin irritation and cardiomyopathy; risk of dilated cardiomyopathy is reduced by • dexrazoxane (an iron-chelating agent) • Methotrexate May cause severe mucositis and myelosuppression, which is prevented by the use of folinic • acid rescue. During chronic administration, pneumonitis and liver fibrosis may occur • Vincristine and vinblastine • Cause a reversible peripheral neuropathy Retinoids Oral retinoids are indicated for the treatment of severe psoriasis and acne that is resistant to other therapies. They are teratogenic, leading to neural tube defects. Similar to other vitamin A derivatives they may cause benign intracranial hypertension. Dryness of mucous membranes, leading to intolerance of contact lenses, has been noted during treatment with retinoids. High-dose retinoids can rarely cause diffuse interstitial skeletal hyperostosis, similar to Foriestier’s disease. Adverse effects of retinoids • • • • • • • • • • • Alopecia Photosensitivity Benign intracranial hypertension Reduced night vision Dry mucous membranes Skeletal abnormalities (with high doses) Hepatitis Hypertriglyceridaemia Teratogenicity Mood changes Thrombocytopenia Strontium Strontium ranelate is licensed for postmenopausal osteoporosis. It increases new bone formation and suppresses bone resorption. Recognised adverse effects include severe allergy and drug rash with eosinophilia and systemic symptoms (DRESS). 2.5 SPECIFIC ADVERSE EFFECTS 2.5.1 Secondary amenorrhoea Dopamine inhibits prolactin release, so dopamine-blocking drugs, such as chlorpromazine and cimetidine (but not ranitidine), may provoke hyperprolactinaemia and hence amenorrhoea. Sodium valproate may also cause amenorrhoea. 2.5.2 Bronchospasm Bronchospasm may be induced by aspirin and NSAIDs, particularly in patients with late-onset asthma. Sensitivity to these agents relates to pharmacological effects on prostaglandin metabolism; the effect is a non-IgE anaphylactic mechanism. Adenosine causes bronchoconstriction via adenosine receptors within the bronchial smooth muscle, and it should be avoided in patients with asthma • β Blockers (even cardioselective ones such as nebivolol) may provoke bronchospasm • Sodium cromoglicate is a mast-cell stabiliser; it is an inhaled, preventive agent in asthma. • However, bronchospasm has occasionally been reported, because cromoglicate is administered as a dry powder • Acetylcysteine may cause bronchospasm and non-IgE-mediated anaphylaxis. 2.5.3 Dyskinesia and dystonia Both dopamine agonists and antagonists can lead to movement disorders: Drugs with dopamine-like effects that are used to treat Parkinson’s disease may cause dyskinesia (L-dopa, bromocriptine and pergolide) Dopamine-blocking agents such as phenothiazines (chlorpromazine) or butyrophenones (haloperidol) may also cause dyskinesias. This is a recognised complication of treatment with • dopamine antagonists such as metoclopramide. It is less common with domperidone due to poorer uptake of this agent across the blood–brain barrier SSRIs may cause dystonias and rarely are associated with serotoninergic syndromes which are a group of clinical disorders characterized by excess serotonergic effects, often occurring when • SSRI combined with another drug capable of exerting effects on serotonergic pathways eg tramadol, tricyclics, antipsychotics. • 2.5.4 Gynaecomastia Gynaecomastia can complicate treatment with drugs that are oestrogen-like in action or antiandrogens. Oestrogen-like action Digoxin spironolactone diethylstilbestrol Anti-androgen action Cimetidine Cyproterone acetate Luteinising hormone-releasing hormone (LHRH) analogues (eg goserelin) 2.5.5 Hypothyroidism Impaired thyroid hormone production may result from the following: • • • • amiodarone carbimazole lithium propylthiouracil • radioiodine. Others: sulfonamides, sulfonylureas and ketoconazole inhibit iodination and iodotyrosine coupling within the thyroid gland. Lithium inhibits iodide transport into the thyroid gland and inhibits thyroid function. 2.5.6 Drug-induced liver injury Drug-induced liver injury may represent either dose-dependent or dose-independent effects. Dose-dependent liver injury includes paracetamol poisoning, fatty change due to tetracycline or alcoholic hepatitis Dose-independent liver injury usually involves either hepatitis or cholestasis; it generally has an • allergic basis and may on occasion be associated with liver failure Liver tumours may be associated with use of androgens and oestrogens (which can also cause • Budd–Chiari malformations); liver fibrosis may accompany methotrexate treatment. • Drug-induced hepatitis occurs with • • • • • • • • • Amiodarone Exanetide HMG-CoA reductase inhibitors Isoniazid metabolite Methyldopa Paracetamol Phenytoin Pyrazinamide Valproate (especially in patients receiving other antiepileptics and those aged <2 years) Causes of drug-induced cholestasis • • • • • • Carbamazepine Chlorpromazine Co-amoxiclav (combination of amoxicillin and clavulanic acid) Erythromycin Flucloxacillin Sulfonylureas 2.5.7 Drugs provoking myasthenia Aminoglycosides, certain β blockers (propranolol, oxprenolol), phenytoin, lidocaine, quinidine • and procainamide may all impair acetylcholine release, leading to worsening or unmasking of myasthenia Penicillamine may cause formation of antibodies against the acetylcholine receptor, and a • syndrome indistinguishable from myasthenia results. This resolves in two-thirds of cases after penicillamine withdrawal • Lithium may also cause myasthenia-like weakness by impairing synaptic transmission. 2.5.8 Photosensitivity Drugs causing photosensitivity • • • • • • • • • • Amiodarone Piroxicam Ciprofloxacin Psoralens Griseofulvin Retinoids Loop and thiazide diuretics Sulfonylureas Oral contraceptives Tetracyclines 2.5.9 Drug-induced vasculitis Drug-induced vasculitis can affect the skin or internal organs. Recognised drug causes of vasculitis • • • • • • • Allopurinol Captopril Cimetidine Hydralazine Leukotriene antagonists Penicillin Quinidine • Sulfonamides • Thiazides 2.5.10 Acute pancreatitis Acute pancreatitis is a recognised adverse effect of a number of drugs. Drugs causing acute pancreatitis • • • • • • • Antiretrovirals (ritonavir, didanosine, zalcitabine, stavudine, lamivudine) Azathioprine Corticosteroids Fibrates HMG-CoA reductase inhibitors Omega-3 fish oils Thiazide diuretics 2.5.11 Syndrome of inappropriate ADH secretion SIADH is characterised by hyponatraemia, concentrated urine and low plasma osmolality, all occurring in the absence of oedema, diuretic use or hypovolaemia. Treatment involves cessation of the responsible drug and, in persistent cases, demeclocycline may be considered. Drugs causing SIADH • • • • • • • Carbamazepine Chlorpropamide Cytotoxic agents Opiates Oxytocin Psychotropic agents Rifampicin In addition, there are a number of non-pharmacological causes, which include malignancy, CNS disorders, suppurative pulmonary disease and porphyria. (See Chapter 4, Endocrinology, Section 4.4.) 2.5.12 Drug-induced diabetes insipidus Drug-induced diabetes insipidus is generally nephrogenic, namely diminished responsiveness of the kidneys to ADH and an impaired ability to concentrate urine. Lithium is the most common cause, affecting around 10% of patients treated for >15 years; the risk is minimised by limiting treatment to a maximum of 5 years, and maintaining 12-hour trough serum concentrations between 0.4 and 0.6 mmol/L. Other recognised drugs include foscarnet, clozapine, amphotericin B, orlistat, ifosfomide and cidofovir. Management involves stopping the offending drug, and some patients may respond to treatment with thiazide diuretics, amiloride or NSAIDs. 2.6 POISONING 2.6.1 Paracetamol overdose Paracetamol overdose is one of the most common means of self-poisoning. Early features are minor (nausea and vomiting). Acute liver injury may occur later, typically with peak transaminases at 2–3 days after ingestion, but fulminant liver may occur in severe poisoning. Toxicity is thought to be due to excess reactive oxygen species and a paracetamol metabolite that binds to liver cell macromolecules causing necrosis. • • • • • • • The international normalised ratio (INR), or prothrombin ratio, is the most sensitive indicator of impaired liver function. Hypoglycaemia is a feature of advanced liver damage Poor prognosis is indicated by an INR >3.0, raised serum creatinine and plasma pH <7.3 more than 24 hours after overdose Acute kidney injury may occur, onset is typically 2–3 days after ingestion and may occur in the absence of liver injury Acetylcysteine improves prognosis in paracetamol poisoning even after hepatic encephalopathy has developed Paracetamol concentrations determined at 4 to 15 hours after an acute single time-point overdose may be used to estimate the extent of drug exposure by comparison to a standardised nomogram: acetylcysteine antidote is indicated in all patients with paracetamol concentration higher than the treatment nomogram The nomogram approach cannot be applied if patients present to hospital >15 hours after acute overdose, or if patients have taken multiple paracetamol ingestions, or have taken a prolonged overdose >1 hour, so-called staggered ingestion: in these cases, the need for antidote is based upon clinical judgement and the stated dose ingested A small number of patients will develop fulminant hepatic failure despite paracetamol concentrations lower than the treatment nomogram, so that in some countries all patients that present to hospital after paracetamol overdose receive antidote treament. 2.6.2 Tricyclic antidepressant and venlafaxine overdose Tricyclic antidepressants and venlafaxine exert a number of toxic effects: • • • • Anticholinergic effects: pupillary dilatation, acute confusion, tachycardia, dry mouth α-Blocking effects: systemic hypotension and reduced conscious level Sodium channel blockade: arrhythmia and seizures Prolongation of the QRS complex >100 ms may be associated with increased risk of arrhythmia Seizure threshold is reduced and status epilepticus may occur; abnormalities of thermoregulation • can also occur Treatment is supportive, and activated charcoal should be considered if <1 hour after ingestion and airway protected. Seizures should be treated with benzodiazepines. Intravenous sodium • bicarbonate reduces the risk of arrhythmias and seizures and should be considered for patients at high risk (reduced conscious level, acidosis, QRS duration >100 ms) • Duration of venlafaxine toxicity may be prolonged for up to 48 hours after ingestion of standardrelease preparations and up to 72 hours after overdose involving modified-release formulations. 2.6.3 Theophylline toxicity This may cause tachyarrhythmia due to phosphodiesterase inhibition. Electrolyte abnormalities include severe acidosis and hypokalaemia (the latter partly due to intractable vomiting). Reduced conscious level, seizures and confusion may also occur. Treatment is with repeated doses of oral activated charcoal (which significantly enhances theophylline clearance), and correction of fluid and electrolyte depletion • Haemodialysis is indicated for patients with severe toxicity (plasma theophylline >60 mg/L). • 2.6.4 Carbon monoxide poisoning Carbon monoxide binds to haemoglobin with high affinity (200 times that of oxygen), and decreases oxygen-carrying capacity, resulting in tissue hypoxia. Normal carboxyhaemoglobin levels are <3% in non-smokers and 5–6% in smokers. Mild exposure (10–30% carboxyhaemoglobin) may be associated with headache and mild exertional dyspnoea. Signs of marked toxicity (carboxyhaemoglobin 30–60%) • • • • • • • • Acute renal failure Agitation and confusion Bullous lesions ECG changes and arrhythmias Hyperpyrexia Hypertonia and hyperreflexia Muscle necrosis Pink mucosae • Vomiting • Severe toxicity may be associated with coma, convulsions and cardiorespiratory arrest Treatment is with 100% oxygen by mask; hyperbaric oxygen (2.5 atmospheres pressure) will • increase the elimination (half-life reduced from 4 hours to 0.5 hour) Neuropsychiatric changes may develop over several weeks after recovery from poisoning and • these include intellectual deterioration, personality change, cerebral and cerebellar damage, and extrapyramidal damage. 2.6.5 Quinine toxicity Quinine poisoning may result in visual disturbance due to anticholinergic effects and direct neurotoxicity. Blindness may occur at between 6 and 24 hours after ingestion, and may be irreversible. • • • • • Arrhythmias: increased risk of QT prolongation and torsades de pointes Hypotension: may occur due to α-adrenoceptor blockade Tinnitus Severe metabolic acidosis Abdominal pain. 2.6.6 Iron poisoning The key features of iron poisoning are shown in the box below. Gastric lavage should be contemplated if the patient presents within 1 hour of life-threatening ingestion. Desferrioxamine chelates iron and may improve clinical outcome when given by intravenous infusion. The decision to administer desferrioxamine is based on the serum iron concentration, although in severe symptomatic cases it may be started before this is available. Clinical features • • • • • Abdominal pain Diarrhoea Haematemesis Lower gastrointestinal blood loss Nausea and vomiting Severe poisoning • Coma • • • • Death Delayed hepatocellular necrosis Metabolic acidosis Hypotension 2.6.7 Salicylate overdose In early salicylate poisoning there is direct stimulation of the CNS respiratory centre causing a tachypnoea, ‘air hunger’ and respiratory alkalosis. As systemic aspirin absorption progresses, patients may develop a metabolic acidosis that can be severe or fatal. Early features of poisoning • • • • Hypokalaemia Respiratory centre stimulation in the CNS, and hence alkalosis Sweating Tinnitus Later features of poisoning • • • • • Acute renal failure Hypoglycaemia Hypoprothrombinaemia Metabolic acidosis Pulmonary oedema Key aspects of management of salicylate poisoning involve the following: • Activated charcoal • Correction of electrolyte and metabolic abnormalities Intravenous fluids to ensure adequate hydration (forced alkaline diuresis is unsafe and not • recommended) Intravenous sodium bicarbonate to correct acidosis (this will reduce the quantity of salicylate • taken up into tissues, and may enhance renal clearance of aspirin) • Haemodialysis: for very severe salicylism (eg blood salicylate >750 mg/L). 2.6.8 Ethylene glycol poisoning Poisoning with ethylene glycol may have a similar clinical appearance to ethanol intoxication, within the first 12 hours. Initially there is a raised plasma osmolar gap due to the presence of ethylene glycol. This is then broken down, the degradation products, including oxalate, giving rise to a metabolic acidosis with a wide anion gap. Toxic effects include severe metabolic acidosis, hypocalcaemia, acute tubular necrosis, crystalluria, and cardiac failure and pulmonary oedema. Treatment for ethylene glycol poisoning • Sodium bicarbonate • To correct acidosis and enhance clearance of active metabolites • Intravenous ethanol • Can inhibit ethylene glycol metabolism • Fomepizole This blocks the conversion of ethylene glycol to toxic metabolites, so that ethylene glycol may • be excreted unchanged • Calcium • To correct hypocalcaemia • Haemodialysis • Active elimination of ethylene glycol is by haemodialysis 2.6.9 Haemodialysis for overdose or poisoning Certain drugs and poisons may be effectively removed by haemodialysis, particularly those with a low volume of distribution that are largely confined to the circulating compartment. Conversely, haemodialysis is ineffective for drugs with a wide volume of distribution (eg amiodarone and paraquat), or those that are highly protein bound (eg digoxin and phenytoin). Repeated or continuous dialysis treatment for >16 hours may be required for drugs that are distributed throughout the extracellular fluid compartment (eg lithium), and a rebound increase in plasma concentrations may occur after shorter periods of dialysis. There are limited data concerning the impact of haemodialysis on patient outcomes, and it is normally only undertaken in patients with severe poisoning by selected agents. Removal of drugs or toxins by haemodialysis/haemoperfusion • • • • Barbiturates Ethanol Ethylene glycol Lithium • Methanol • Salicylate Chapter 3 Dermatology CONTENTS 3.1 Structure and function of skin and terminology of skin lesions 3.1.1 Structure 3.1.2 Function 3.1.3 Terminology of skin lesions 3.2 Specific dermatoses and infections of the skin 3.2.1 Psoriasis 3.2.2 Eczema (dermatitis) 3.2.3 Acne 3.2.4 Rosacea 3.2.5 Lichen planus 3.2.6 Erythema multiforme 3.2.7 Erythema nodosum 3.2.8 Specific skin infections 3.3 Bullous eruptions 3.4 The skin in connective tissue disorders 3.4.1 Systemic sclerosis 3.4.2 Rheumatoid arthritis 3.4.3 Dermatomyositis 3.4.4 Lupus erythematosus 3.5 The skin in other systemic diseases 3.5.1 Sarcoidosis 3.5.2 The porphyrias 3.5.3 Pyoderma gangrenosum 3.5.4 Diabetes 3.6 Generalised pruritus 3.7 Cutaneous markers of internal malignancy 3.7.1 Genetically determined syndromes with skin manifestations 3.7.2 Skin signs as paraneoplastic features 3.8 Disorders of pigmentation 3.9 Drug eruptions 3.10 Urticaria 3.11 Skin tumours 3.11.1 Malignant melanoma 3.11.2 Basal cell carcinoma 3.11.3 Squamous cell carcinoma 3.11.4 Other skin tumours 3.12 Hair and nails 3.12.1 Disorders of hair 3.12.2 Disorders of nails Dermatology 3.1 STRUCTURE AND FUNCTION OF SKIN AND TERMINOLOGY OF SKIN LESIONS 3.1.1 Structure The skin consists of three distinctive layers: the epidermis, dermis and the subcutis. • • • • Epidermis: this forms the outermost layer and is the largest organ in the body. The principal cell is the keratinocyte. The epidermis has four layers, which are the basal cell layer, stratum spinosum, stratum granulosum and the stratum corneum Dermis: this lies beneath the epidermis and is a support structurally and nutritionally, and contributes 15–20% of total body weight. The principal cell is the fibroblast, which makes collagen (giving the skin its strength), elastin (providing elasticity) and proteoglycans. It also contains adnexal structures, including hair follicles, sebaceous glands, apocrine glands and eccrine glands Dermoepidermal junction: separates the epidermis from the dermis. Anomalies of this can give rise to some of the blistering disorders Subcutis: contains adipose tissue, loose connective tissue, blood vessels and nerves. 3.1.2 Function The skin has numerous functions, all of which are designed to protect the rest of the body. • • • • • Barrier properties: the skin acts as a two-way barrier, preventing the inward or outward passage of fluid and electrolytes Mechanical properties: the skin is highly elastic and so can be stretched or compressed Immunological function: the skin provides defence against foreign agents. In the epidermis, antigen presentation is carried out by Langerhans’ cells Sensory function: the skin perceives the sensations of touch, pressure, cold, warmth and pain Endocrine properties: as a result of exposure to ultraviolet B radiation, vitamin D3 is synthesised from previtamin D3 Temperature regulation: the rich blood supply of the dermis plays an important role in thermoregulation • Respiration: the skin plays a minor role in gaseous exchange with the environment. • 3.1.3 • • • • • • • • • • Terminology of skin lesions Macule: a flat lesion due to a localised colour change; when >1 cm in diameter, this is termed a ‘patch’ Papule: a small solid elevation of skin <1 cm diameter Plaque: a raised flat-topped lesion >1 cm diameter Nodule: a raised lesion with a rounded surface >1 cm diameter Bulla: a fluid-filled lesion (blister) >1 cm diameter Vesicle: a fluid-filled skin lesion <1 cm diameter Pustule: a pus-filled lesion Weal: a raised compressible area of dermal oedema Scale: flakes arising from abnormal stratum corneum Crust: dried serum, pus or blood. 3.2 SPECIFIC DERMATOSES AND INFECTIONS OF THE SKIN 3.2.1 Psoriasis This is an immune-mediated, chronic, multisystem inflammatory disease occurring in 1–2% of the UK population. It affects both genders equally and occurs at any age, with two peak age ranges (16–22 and 57–60 years). Its aetiology is unknown but multiple genetic factors in combination with environmental factors are thought to be important. Of individuals with psoriasis, 30% have an affected first-degree relative, and the risk of a child developing psoriasis if both parents are affected is 75%. A number of psoriasis-susceptibility gene loci (eg PSOR1) and genes involved in interleukin (IL)-23 signalling, modulation of T-helper (Th)-2 immune responses (IL-4, IL-13) and activated B-cell (NFκB) signalling have been identified. The understanding of psoriasis has moved from one of a hyperkeratotic disorder of keratinocytes to a dysregulation of the immune system mediated by cytokines. It is now understood that Th-1, Th-17 and Th-22 cell populations are expanded and stimulated to release inflammatory cytokines, including IL-17, IL-22 and tumour necrosis factor α (TNF-α). Clinical presentation Chronic plaque (90% of cases): well-defined, red, disc-like plaques covered by white scale, which classically affect elbows, knees and scalp Pustular (generalised pustular): sheets of small, sterile yellow pustules on a red background. • This presentation may be accompanied by systemic symptoms and progression to erythroderma • Erythrodermic: confluent areas affecting most of the skin surface • Nail psoriasis: onycholysis, pitting and subungal hyperkeratosis Pustular (palmoplantar pustulosis): yellow/brown sterile pustules and erythema on palms or • • soles. Strongly associated with smoking. This is most often seen in middle-aged women • Guttate: an acute eruption of drop-like lesions, often following a streptococcal sore throat • Flexural: affects axillae, submammary areas and the natal cleft. Lesions are often smooth, red and glazed in appearance. Associations with psoriasis Psoriasis is now known to be a systemic disease mediated via T cells; the inflammatory processes involved are associated with the development of a number of co-morbidities as well as reduced life expectancy. • • • • • Major cardiac adverse events (MACE): studies show that patients with psoriasis have a 53% increased incidence of MACE (MI, stroke, cardiac death) compared with the general population. There is known to be an increased risk of cardiovascular disease independent of other risk factors, however. Psoriasis is also strongly associated with the metabolic syndrome (hypertension, obesity, diabetes and dyslipidaemia). Obesity has been shown to be a risk factor for the development of psoriasis and an increasing body mass index (BMI) is associated with greater degrees of severity. Psoriasis of any type, especially if severe, is a risk factor for venous thromboembolism. Arthropathy: psoriatic arthritis occurs in about 20% of patients with psoriasis. There are several different forms (see Chapter 20) – distal interphalangeal joint disease, large single-joint oligoarthritis, arthritis mutilans, sacroiliitis and psoriatic spondylitis have all been described Gout: this is due to deposits of urate crystals Malabsorption: Crohn’s disease and ulcerative colitis are associated with psoriasis Lymphoma: there is a reported threefold increase in the rates of lymphoma in psoriasis patients. Factors that can exacerbate psoriasis • Trauma: the Köbner phenomenon (the development of the disease in areas of trauma) • Infection: eg streptococci (guttate psoriasis, as above) HIV: psoriasis is more common in patients with HIV; the severity may dwindle in the late stages • of the disease Endocrine: psoriasis generally tends to improve during pregnancy and deteriorate in the post• partum period Drugs: β blockers, lithium, antimalarials, interferon and the withdrawal of oral steroids can • exacerbate psoriasis • Alcohol • Stress: most patients report a flare of disease with physical or psychological stress Smoking: smokers have an increased risk of psoriasis and heavy smokers have more severe • disease UV light: although most patients find UV light beneficial, a small proportion find it flares their • skin condition. Causes of the Köbner phenomenon • • • • • Psoriasis Lichen planus Vitiligo Viral warts Molluscum contagiosum Causes of erythroderma • • • • • • Psoriasis Eczema Mycosis fungoides Adverse drug reactions Underlying malignancy Pityriasis rubra pilaris Management of psoriasis Offer people with any type of psoriasis support and information tailored to suit their individual needs and circumstances, in a range of different formats, so that they can confidently understand the following: • • • • • Their diagnosis and treatment options Relevant lifestyle risk factors When and how to use prescribed treatments safely and effectively When and how to seek further general or specialist review Strategies to deal with the impact of psoriasis on physical, psychological and social wellbeing Assess the following: • • • • Disease severity The impact of disease on physical, psychological and social wellbeing Whether they have psoriatic arthritis The presence of co-morbidities. First-line treatment: topical therapy Coal tar preparations: available over the counter in weak forms; crude coal tar can be useful in thick plaque psoriasis Dithranol: a synthetic derivative of anthracene. It is an effective therapy but needs to be applied • accurately because it can stain clothing and burn surrounding skin • • Vitamin D analogues, eg calcipotriol cream or ointment or calcipotriol with betamethasone • Tarazotene: a topical retinoid for plaque psoriasis Topical steroids: may be used solely or in combination with other topicals for face, genitalia, • flexures, hands and feet, and scalp. The strength of steroid varies according to the body site and severity. Second-line treatment Offer phototherapy or non-biological systemic agents when topical therapy alone is unlikely to control disease (eg extensive disease <10% body surface area [BSA], or nail disease and the disease has a significant impact on physical, psychological or social wellbeing), psoriasis is extensive (eg >10% BSA affected or a psoriasis area severity index [PASI] score >10) psoriasis is localised and associated with significant functional impairment and/or high levels of distress (eg severe nail disease or involvement at high-impact sites) or phototherapy has been ineffective, cannot be used or has resulted in rapid relapse (rapid relapse is defined as >50% of baseline disease severity within 3 months). Phototherapy (ultraviolet radiation) • UVB narrowband (311–313 nm) is a well-established and effective treatment PUVA (oral/topical psoralen and UVA): oral psoralen use necessitates the need for protective • eyewear and is associated with an increase risk of skin cancers. Non-biological systemic treatment The benefits must be weighed against the side-effects of the drugs. Methotrexate is used as a first-line non-biological systemic treatment; it blocks DNA synthesis by inhibiting dihydrofolate reductase. It is administered once weekly, orally or subcutaneously. The risks of nausea, anaemia and pancytopenia are reduced with folic acid supplementation. There is a risk of liver fibrosis with long-term use. A serological marker for fibrosis, amino-terminal peptide procollagen III (P3NP), is measured 3-monthly and a liver biopsy is performed if consistently high, further evaluation of liver fibrosis may be indicated. Ciclosporin: is used as a first-line non-biological systemic treatment particularly where rapid or short-term disease control is required, there is palmoplantar pustulosis or conception is being considered (in men and women in whom systemic treatment cannot be avoided); it inhibits Tlymphocyte transcription of IL-2. Major side-effects are renal toxicity and hypertension. Retinoids: acitretin is the retinoid of choice and is used alone or in combination with UVB or PUVA. Teratogenicity is a problem and treatment should be avoided in women of childbearing potential. Mucocutaneous side-effects are common and elevated triglyceride levels are often observed. Treatments used less commonly include: azathioprine, hydroxyurea, mycophenolate mofetil (MMF) and fumaric acid esters. Third-line treatment: biologic agents Biologics are considered for patients with severe disease. Strict eligibility criteria are in place and patients may have been unresponsive/intolerant to standard systemic and phototherapy, systemic therapy may be contraindicated or they may have severe life-threatening disease. A PASI score is a tool used to measure the extent and the severity of the psoriasis and a DLQI (dermatology life quality index) assesses the impact of the disease on quality of life. For biological treatment these scores must be at least 10. The current National Institute for Health and Care Excellence (NICE)-approved biologics target TNF-α or the interleukin pathway is as follows: Etanercept: human fusion protein of the TNF receptor that acts as a TNF-α inhibitor. Delivered subcutaneously • Adalimumab: a human monoclonal antibody that binds to TNF-α. Delivered subcutaneously • Infliximab: a chimeric monoclonal antibody that binds to TNF-α. Delivered by infusion Ustekinumab: a human monoclonal antibody that targets IL-12 and IL-23. Delivered • subcutaneously. • Other biologic agents are in development, but at this stage are not NICE approved. 3.2.2 Eczema (dermatitis) Eczema is an inflammatory skin disorder with characteristic histology and clinical features, which include itching, redness, scaling and a papulovesicular rash. Eczema can be divided into two broad groups, exogenous or endogenous: • Exogenous eczema: irritant dermatitis, allergic contact dermatitis • Endogenous eczema: atopic dermatitis, seborrhoeic dermatitis, pompholyx. Seborrhoeic dermatitis is a red, scaly rash caused by Pityrosporum ovale. The eruption occurs on the scalp, face and upper trunk, and is more common in young adults and patients with HIV. Pompholyx is characterised by itchy vesicles occurring on the palms and soles. Atopic dermatitis affects 20–30% of the UK population. It is a characteristic dermatitic eruption associated with a personal or family history of atopy. Both genetic and environmental factors interact to contribute to pathogenesis, with convincing evidence of both a barrier defect (caused by a compromise in epidermal permeability through null mutations in the filaggrin gene) and a Th-2-driven cutaneous inflammatory response. Management of atopic eczema Initial treatment consists of avoidance of irritants and exacerbating factors. Thereafter: Topical therapy: regular emollients, topical steroids, tar bandages, wet wraps and antibiotic ointment (for minor infections). Topical calcineurin inhibitors are considered when treatment has • failed with the appropriate strength of topical steroid or there is a risk of skin atrophy. Tacrolimus is used for moderate-to-severe eczema in children age >2 and adults. Pimecrolimus is used for the face and neck of children aged >2 • Ultraviolet radiation: UVB or PUVA (see Psoriasis, section 3.2.1) Systemic treatment: this can be with ciclosporin, azathioprine and antihistamines, as well as • antibiotics for any infective episodes. Occasionally oral prednisolone is used for severe flares. Alitretinoin is an oral retinoid licensed for hand dermatitis; unresponsive to topical steroids. 3.2.3 Acne Acne is the most common of the dermatological disorders and affects most people at some time during their life. Although not life-threatening, acne can have severe psychosocial consequences and may lead to poor self-esteem, social isolation and depression. Pathogenesis Acne has a multifactorial pathogenesis and results from the interplay of the following four factors: 1. Plugging of the follicle due to epidermal proliferation 2. Excess sebum production 3. Colonisation with Propionibacterium acnes 4. Inflammation. Clinical features Acne is characterised by comedones, papules, pustules, nodules, cysts and scars. It affects the areas of skin where the sebaceous follicles are most dense: the face, back and chest. Treatment Choice of treatment should be based on the severity of the disease and the type of acne, eg comedonal, non-inflammatory acne may require only a keratolytic agent. Most moderate-grade acne needs a combined approach to treat both the comedones and the inflammatory lesions. Topical treatments Topical antibiotics: these are not comedolytic and are best used in combination with benzoyl peroxide or another keratolytic agent Topical retinoids: comedolytic and anti-inflammatory. They may be used in combination with • other acne medications. They often cause skin irritation • Benzoyl peroxide: a keratolytic that comes in many formulations • Azelaic acid: keratolytic and anti-inflammatory. • Systemic treatments • Antibiotics: tetracyclines or erythromycin should be considered with moderate acne, especially if there is a risk of scarring Combined oral contraceptive: a standard combined oral contraceptive should be considered in • all women with acne who require contraception or in whom there is a suspected hormonal basis for the acne. Co-cyprindiol (Dianette), a combination of ethinylestradiol and the anti-androgen cyproterone, may be considered Isotretinoin: a systemic retinoid that is highly effective. It is indicated if there is scarring, if the acne is resistant to multiple treatments (including long-term systemic antibiotics) or if the disease is causing severe psychological distress. Isotretinoin is a teratogen and strict guidelines for its • use and prescription are now in place. Women of childbearing age are advised to use two methods of contraception and to have monthly pregnancy testing. The most common side-effects are mucocutaneous, with severe drying of lips and skin. Mood changes and severe depression have been reported. 3.2.4 Rosacea Rosacea is an inflammatory skin disease that causes erythema, telangiectasia, inflammatory papules and pustules. The skin tends to be dry and sensitive. It may cause flushing and in severe cases rhinophyma (usually in men). Ocular rosacea may occur and cause blepharitis, conjunctivitis or keratitis. Trigger factors include alcohol, sunlight, exercise, high and low temperatures, and spicy foods. Treatment Topical Topical metronidazole or azelaic acid may help to control inflammation in mild-to-moderate rosacea. Mirvaso is a new treatment for the erythema of rosacea. The active ingredient brimonidine (α2 agonist) causes vasoconstriction. Systemic Most commonly, tetracyclines or erythromycin are used. A third of patients respond to 2 months of treatment. Many patients need long-term treatment. A β blocker or clonidine may help flushing. In severe, resistant cases isotretinoin may be used. 3.2.5 Lichen planus This presents as an itchy, shiny, violaceous, flattopped, polygonal, papular rash with white lines on the surface known as Wickham’s striae. Other affected sites include mucous membranes, genitalia, palms, soles, scalp and nails. Lichen planus causes a white lace-like pattern on the buccal mucosa. Causes of white lesions in the oral mucosa • • • • Lichen planus Leukoplakia Chronic candidiasis Chemical burns. 3.2.6 Erythema multiforme This is usually a maculopapular, targetoid rash, which can occur anywhere, including the palms, soles and oral mucosa. The cause is unknown but it is thought to be associated with infections, mainly viral. Stevens–Johnson syndrome, on the other hand, is more likely to affect mucosal surfaces and is believed to be associated with drug reactions. Causes of erythema multiforme • • • Infections • Herpes simplex virus • Mycoplasma spp. • Psittacosis • Rickettsia spp. • HIV • Hepatitis B virus • Orf • Infectious mononucleosis • Mumps Drug reactions • Barbiturates • Penicillin • Sulfonamides Others • Lupus erythematosus • Polyarteritis nodosa • Wegener’s granulomatosis • Underlying malignancy • Sarcoidosis 3.2.7 Erythema nodosum This is a hot, tender, nodular, erythematous eruption lasting 3–6 weeks, which is more common in the third decade and in females. Causes of erythema nodosum • Bacterial infection • Streptococcal throat infection (commonly) • • • • • • • Salmonellae • Campylobacters • Tuberculosis • Mycoplasma pneumoniae • Yersinia enterocolitica Mycoses • Coccidioidomycosis • Histoplasmosis • Blastomycosis Inflammatory bowel disease Sarcoidosis • Behçet’s syndrome Drugs • Penicillin • Tetracyclines • Oral contraceptive pill • Sulfonamides • Sulfonylureas Malignancy • Hodgkin’s lymphoma • Acute myelocytic leukaemia Pregnancy • Viral infection 3.2.8 Specific skin infections These can be subdivided into bacterial, fungal and viral infections as well as infestations. Specific infections of the skin • Bacterial infections Streptococcal: cellulitis, erysipelas, impetigo, necrotising fasciitis, rheumatic fever • (erythema marginatum), scarlet fever Staphylococcal: folliculitis, impetigo, staphylococcal scalded-skin syndrome, toxic shock • syndrome Mycobacterial: TB (lupus vulgaris, scrofuloderma), fish-tank granuloma, Buruli’s ulcer, • leprosy • • • • Spirochaetal: syphilis, Lyme disease (erythema chronicum migrans) Fungal Dermatophytes: Trichophyton rubrum, T. interdigitale, Epidermophyton floccosum (tinea • pedis, tinea corporis, tinea cruris, tinea unguium) Yeasts: Candida spp. (intertrigo, oral, genital or systemic); Pityrosporum orbiculare; • pityriasis versicolor Viral • Human papillomavirus: warts Herpes virus: varicella (chickenpox), zoster (shingles), simplex 1 (face and lips), simplex • 2 (genital) • Pox virus: molluscum contagiosum, parapox virus (orf) • Parvovirus B19: erythema infectiosum (fifth disease) • RNA virus: measles, rubella • Coxsackie A16 virus: hand, foot and mouth disease HIV/AIDS: skin disease is common, affecting 75% of patients, who can be at any stage of • HIV disease (see Chapter 8) Infestations • Sarcoptes scabiei: scabies mite infestation • Lice infestation (pediculosis): head lice, pubic lice 3.3 BULLOUS ERUPTIONS This is a rare group of disorders characterised by the formation of bullae. The development of blisters can be due to congenital, immunological or other causes. The level of split within the epidermis or within the dermoepidermal junction determines the type of bullous disorder. Causes of bullous eruptions • • • Congenital • Epidermolysis bullosa Others • Streptococcal infection • Staphylococcal scalded-skin syndrome • Toxic epidermal necrolysis • Diabetic bullae • Chronic renal failure • Haemodialysis Immunological • • Pemphigus • Bullous pemphigoid • Cicatricial pemphigoid • Herpes gestationis • Dermatitis herpetiformis Drug overdose • Barbiturates Epidermolysis bullosa (EB) is the term used for a clinically and genetically heterogeneous group of rare inherited disorders characterised by fragility and blistering of skin and mucosae. It is caused by mutations involving at least 18 genes encoding structural proteins in the skin and mucosae. There are three main types: 1. EB simplex: 70% of cases and tends to be the mildest form 2. Junctional EB: 5% of cases and considered the most severe form Dystrophic EB: symptoms vary widely but severe cases can result in loss of vision, scarring, 3. disfigurement, skin cancer and gastrointestinal tract blistering. Pemphigus is a rare group of disorders characterised by blistering of the skin and mucous membranes. The bullae are superficial and confined to the epidermal layer. Pathogenic IgG autoantibodies bind to transmembrane desmosomal proteins of keratinocytes called desmogleins. The binding process results in loss of cell-to-cell adhesion and the production of superficial bullae in the epidermal layer. These superficial bullae rupture easily. Three major variants have been described: Pemphigus vulgaris is the most common variant and accounts for 70% of cases; there are 1. autoantibodies to desmoglein 1 and desmoglein 3. It most commonly presents with painful erosions or blisters on the oral mucosa; skin lesions may present months later Pemphigus foliaceus is generally a benign variant and is characterised by lesions that occur only 2. in the skin and is associated with antibodies to desmoglein 1 3. Paraneoplastic pemphigus presents in association with a tumour which may be occult. Untreated, the mortality rate associated with pemphigus vulgaris was 75%. The use of corticosteroids and adjuvant drugs has reduced the mortality rate significantly. It has been reported as 12% in the UK, with a three times higher risk of death than age-matched controls. Bullous pemphigoid is more common than pemphigus. It is a disorder characterised by large, tense blisters found on the limbs, trunk and flexures in elderly people. Oral mucosal involvement is rare. Autoantibodies are present to two hemidesmosomal proteins: BP antigen II (BP180) and BP antigen I (BP230). Cicatricial pemphigoid is a rare, chronic blistering disease of the mucous membranes and skin, which results in permanent scarring, particularly of the conjunctivae. Dermatitis herpetiformis is an itchy, vesiculobullous eruption mainly occurring on the extensor areas. The majority of patients have asymptomatic gluten-sensitive enteropathy. 3.4 THE SKIN IN CONNECTIVE TISSUE DISORDERS 3.4.1 Systemic sclerosis This is a rare, multisystem, connective tissue disease of unknown aetiology, characterised by fibrosis of the skin and visceral organs, and accompanied by the presence of relatively specific antinuclear antibodies. The incidence peaks in the fifth and sixth decades and women are more affected than men (see also Chapter 20, Rheumatology). Morphoea (localised scleroderma) consists of indurated plaques of sclerosis in the skin; systemic features are not found. Skin changes in systemic sclerosis • • • • • • • • • • • • Facial telangiectasia Restricted mouth opening Perioral puckering Smooth, shiny, pigmented indurated skin Raynaud’s phenomenon with gangrene Sclerodactyly Pulp atrophy Dilated nail-fold capillaries Ragged cuticles Calcinosis cutis Livedo reticularis Leg ulcers 3.4.2 Rheumatoid arthritis Specific skin changes in rheumatoid arthritis • • • • Rheumatoid nodules Nail-fold infarcts Vasculitis with gangrene Pyoderma gangrenosum. 3.4.3 Dermatomyositis Specific skin changes in dermatomyositis • Heliotrope rash around eyes • • • • Gottron’s papules: red plaques on extensor surfaces of finger joints Gottron’s sign: erythema over knees and elbows Dilated nail-fold capillaries and prominent, ragged cuticles Nail-fold infarct. 3.4.4 Lupus erythematosus Cutaneous discoid lupus erythematosus is associated with scaly erythematous plaques with follicular plugging on sun-exposed sites. These tend to heal with scarring. Systemic lupus erythematosus (SLE) is commonly associated with dermatological manifestations. These include malar rash, photosensitivity, vasculitis, Raynaud’s phenomenon, alopecia and oropharyngeal ulceration. 3.5 THE SKIN IN OTHER SYSTEMIC DISEASES 3.5.1 Sarcoidosis Skin lesions are found in approximately 25% of patients with systemic sarcoid and can occur in the absence of systemic disease: • • • • Erythema nodosum Scar sarcoid Lupus pernio Scarring alopecia. 3.5.2 The porphyrias Porphyria cutanea tarda: the most common of the porphyrias. Skin signs develop in sunexposed areas. Patients have decreased levels of uroporphyrinogen decarboxylase. Eighty per • cent of cases are acquired, in which case the condition is provoked by a hepatotoxic factor such as alcohol, oestrogens, hepatitis C, iron, lead and certain aromatic hydrocarbon hepatotoxins • Acute intermittent porphyria: skin signs are not seen Congenital erythropoietic porphyria: patients have brown teeth which fluoresce red under • Wood’s light, giving the ‘werewolf’ appearance The typical skin signs of the porphyrias are: • • • • Photosensitivity Blister formation Scarring with milia Hypertrichosis. 3.5.3 Pyoderma gangrenosum This is a painful ulcerating disease of unknown aetiology. It typically affects the legs; it may occur peristomally in inflammatory bowel disease or superficially on the hands. Fifty per cent of cases are associated with underlying medical disorders. Conditions associated with pyoderma gangrenosum • • • • • • Gastrointestinal • Ulcerative colitis • Crohn’s colitis Rheumatological • Rheumatoid arthritis • Ankylosing spondylitis Liver • Chronic active hepatitis • Primary biliary cirrhosis • Sclerosing cholangitis Haematological • Leukaemia • Lymphoma • Myeloproliferative disorders Others • Diabetes mellitus • Thyroid disease • Sarcoidosis • Wegener’s granulomatosis Other malignancies 3.5.4 Diabetes Skin signs in diabetes mellitus • • • • • • Necrobiosis lipoidica Disseminated granuloma annulare Diabetic rubeosis Candidiasis and other infections Vitiligo Neuropathic foot ulcers. Diabetic rubeosis is an odd redness of the face, hands and feet thought to be due to diabetic microangiopathy. 3.6 GENERALISED PRURITUS Pruritus is an important skin symptom and occurs in dermatological diseases such as atopic eczema. In the absence of localised skin disease or skin signs, patients should be fully investigated to exclude an underlying cause. Causes of generalised pruritus • • • • • • • Obstructive liver disease Haematological • Iron-deficiency anaemia • Polycythaemia Endocrine • Hyperthyroidism • Hypothyroidism • Diabetes mellitus Chronic renal failure Malignancy • Internal malignancies • Lymphoma Drugs • Morphine Other • Pregnancy • Senility 3.7 CUTANEOUS MARKERS OF INTERNAL MALIGNANCY There are numerous skin changes associated with internal malignancy. These can be either genetically determined syndromes with cutaneous manifestations, where there is a recognised predisposition to internal malignancy, or paraneoplastic syndromes, where the cutaneous signs are significantly associated with malignancy of various organs. 3.7.1 Genetically determined syndromes with skin manifestations Most of these diseases have an autosomal dominant inheritance. • • • • • • • • • • • • • • • Gardner syndrome: epidermal cysts, lipomas and fibromas are associated with colonic carcinoma Peutz–Jeghers syndrome: mucocutaneous pigmentation is associated with mainly gastrointestinal malignancy Howel–Evans syndrome: tylosis (palmoplantar keratoderma) has been reported with oesophageal carcinoma Torre–Muir syndrome: sebaceous tumours are associated with gastrointestinal malignancy Cowden disease: tricholemmomas (facial nodules) and warty hyperplasia of the mucosal surface is associated with breast and thyroid carcinoma Neurofibromatosis: the presence of six or more café-au-lait macules, axillary freckling and neurofibromas is associated with malignant schwannomas and astrocytomas Tuberous sclerosis: angiofibromas, together with periungual fibromas, shagreen patches and ash-leaf macules are associated with sarcomas and rhabdomyomas Multiple endocrine neoplasia type 2B: mucosal neuromas are associated with medullary thyroid carcinoma and phaeochromocytoma Gorlin syndrome (basal cell naevus syndrome): multiple basal cell carcinomas associated with medulloblastoma, meningioma, astrocytoma and ovarian tumours Von Hippel–Lindau syndrome: café-au-lait macules and haemangiomas are associated with vascular tumours of the central nervous system, phaeochromocytoma, and renal and pancreatic carcinoma Sturge–Weber syndrome: port-wine stain associated with ipsilateral vascular meningeal malformation and epilepsy Wiskott–Aldrich syndrome: a sex-linked recessive disease characterised by eczema, immunodeficiency and an increased risk of lymphoma and leukaemia Chédiak–Higashi syndrome: a fatal autosomal recessive disease with recurrent bacterial infections and widespread infiltration with lymphocytes suggesting a lymphoma Ataxia telangiectasia: an autosomal recessive disease characterised by mucocutaneous telangiectasia and an increased risk of lymphoma and leukaemia Xeroderma pigmentosum: an autosomal recessive group of conditions characterised by multiple melanomas and non-melanoma skin malignancies which start developing from childhood in sunexposed skin. 3.7.2 Skin signs as paraneoplastic features Dermatological features can be seen in all types of malignant disease but some are more common in certain types of neoplasia. Specific dermatological features and the common types of malignancy with which they are associated • • • • • • • • • • • • • • Acanthosis nigricans: gastrointestinal adenocarcinoma Acanthosis palmaris (tripe palms): bronchial carcinoma Acanthosis palmaris with nigricans: gastrointestinal adenocarcinoma Generalised pruritus: lymphoma Dermatomyositis (in adults): bronchial, breast and ovarian tumours Erythema gyratum repens: bronchial carcinoma Acquired hypertrichosis lanuginosa: gastrointestinal and bronchial tumours Necrolytic migratory erythema: glucagonoma Migratory thrombophlebitis: pancreatic carcinoma Acquired ichthyosis: lymphoma Pyoderma gangrenosum: myeloproliferative tumours Erythroderma: lymphoma and leukaemia Clubbing: bronchial carcinoma Herpes zoster: myeloproliferative tumours. Causes of acanthosis nigricans • • • • • • • • • Internal malignancy Acromegaly Cushing syndrome Obesity Insulin-resistant diabetes mellitus Oral contraceptive pill Familial Nicotinic acid Hypothyroidism 3.8 DISORDERS OF PIGMENTATION The major colour determinant of the skin is melanin. This is produced by melanocytes, which are found in the basal layer of the epidermis. Pigmentary disorders usually present with either hypo- or hyperpigmentation. Causes of hypopigmentation • Genetic • Albinism • • • • • • Phenylketonuria • Tuberous sclerosis Chemical • Chloroquine Infections • Pityriasis versicolor Endocrine • Hypopituitarism Autoimmune • Vitiligo Post-inflammatory • Eczema • Psoriasis • Lupus erythematosus Causes of hyperpigmentation • • • • • Genetic • Peutz–Jeghers syndrome • Xeroderma pigmentosum • Albright syndrome Metabolic • Cirrhosis • Haemochromatosis • Porphyria • Renal failure Drugs • Oral contraceptive pill • Minocycline • Amiodarone Endocrine • Addison’s disease • Cushing syndrome • Nelson syndrome • Pregnancy Nutritional • Malabsorption • • Carcinomatosis • Kwashiorkor • Pellagra Post-inflammatory • Lichen planus • Eczema • Secondary syphilis • Cutaneous amyloid 3.9 DRUG ERUPTIONS The incidence of drug eruptions is approximately 2%. The most common drug eruptions are: • • • • • • • • • • Toxic erythema: the most common type of eruption. It is usually characterised by a morbilliform or maculopapular eruption, which may become confluent. Causes include antibiotics (including sulfonamides), carbamazepine, allopurinol, gold, thiazides and anti-tuberculous drugs Fixed drug eruption: this occurs in a localised site each time the drug is administered (see below) Toxic epidermal necrolysis: a life-threatening eruption due to extensive skin loss. This can be associated with allopurinol, sulfonamides, penicillin, carbamazepine, phenytoin, nonsteroidal anti-inflammatory drugs (NSAIDs), gold, salicylates and barbiturates Urticaria: see below Photosensitivity (see Chapter 2, Clinical pharmacology, toxicology and poisoning) Lupus erythematosus-like syndrome: a number of drugs have been implicated as causes of this relatively rare disorder (see Chapter 2, Clinical pharmacology, toxicology and poisoning) Vasculitis: (see Chapter 2, Clinical pharmacology, toxicology and poisoning) Erythema multiforme: this is associated with penicillins, sulfonamides, phenytoin, carbamazepine, angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, gold, barbiturates, thiazides Contact dermatitis Hyperpigmentation (see above): associated with amiodarone, minocycline, bleomycin, chlorpromazine, antimalarials. Drugs that cause a fixed drug eruption • Tetracyclines • Barbiturates • • • • • • • Dapsone Chlordiazepoxide Sulfonamides Benzodiazepines NSAIDs Quinine Paracetamol Diseases aggravated by sunlight • • • • • • • • Lupus erythematosus Dermatomyositis Xeroderma pigmentosum Herpes simplex infection Rosacea Porphyrias (except acute intermittent) Pellagra Carcinoid syndrome 3.10 URTICARIA Urticaria is the term for a group of conditions that involve the onset of itchy weals and may be accompanied by angio-oedema. Acute urticaria is common and usually lasts 24–48 hours. Chronic urticaria lasts for more than 6 weeks, it has a prevalence of 1%. It occurs as chronic spontaneous urticaria (CSU) or is inducible. This group contains physical, cholinergic, contact and aquagenic types. Drugs that cause urticaria • • • • • • • Penicillin Salicylates Quinidine Cephalosporin ACE inhibitors Hydralazine Opiates Management of urticaria Acute: a history may identify a trigger; diagnostic tests are not usually necessary because there is spontaneous remission. CSU: stop any potential triggering drugs, eg NSAIDs; screen for underlying inflammatory disease (ESR/CRP and FBC). Treatment of CSU starts with non-sedating antihistamines, which may be increased to up to four times standard dosing, patients not responding may be treated with montelukast or ciclosporin. Omalizumab (anti-IgE) has recently been shown to be effective in CSU. 3.11 SKIN TUMOURS 3.11.1 Malignant melanoma This has an incidence of around 10/100 000 per year but the rate is doubling every decade. The prognosis is related to tumour thickness. Early lesions are often curable by surgical excision. Melanoma causes the majority (75%) of deaths relating to skin cancer. Any changing mole (bleeding, increase in size, itching, etc) should be viewed suspiciously. The different types of melanoma are: Superficial spreading: this is the most common. An irregularly pigmented macule or plaque which may have an irregular edge and colour variation • Nodular: a pigmented nodule, often rapidly growing and aggressive Lentigo maligna melanoma: occurs in elderly people in a long-standing lentigo maligna (a • slowly expanding, irregularly pigmented macule) Acral lentiginous melanoma: occurs on the palms, soles and nail beds. This is the most common • type of melanoma in Chinese and Japanese people. • Management • • • • Initially lesions suspicious for melanoma are excised with a 2-mm margin A wide local excision is performed, the margin dependent on the Breslow thickness Sentinel lymph node biopsy is used for staging in many centres If lymph node involvement is confirmed, a block dissection may be performed Various chemotherapy agents for metastatic, unresectable disease are used. Vemurafenib (used for patients with a BRAF gene mutation) shows a survival benefit over dacarbazine. Ipilimumab, • a monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), shows the best survival response, with 22% patients alive at 3 years and 17% at 7 years. 3.11.2 Basal cell carcinoma These are the most common skin cancers and are seen most commonly on the face of elderly or middle-aged patients. They only very rarely metastasise. Predisposing factors for basal cell carcinoma (BCC) are: • • • • • Prolonged sun exposure (most common) Radiation treatment Chronic scarring Ingestion of arsenic (tonics) Basal cell naevus syndrome (Gorlin syndrome). Recently, there have been advances in the understanding of the molecular genetics of sporadic BCC. Malfunctioning of the hedgehog-signalling pathway and gene mutations increase the risk of BCC development (the hedgehog pathway influences differentiation of various tissues during fetal development and continues to play a role in cell growth and differentiation in adults). Basal cell carcinomas are classified as: • • • • Nodular/cystic Morphoeic Pigmented Superficial. Management • Surgical excision is the mainstay of treatment • Mohs’ micrographic surgery obtains complete margin control and has a high cure rate • Topical immunotherapy with imiquimod may be used for small, low-risk BCCs. Other treatments include radiotherapy, photodynamic therapy and cryotherapy. Vismodegib is a new systemic agent that targets hedgehog-pathway signalling and is indicated for advanced or metastatic BCC. 3.11.3 Squamous cell carcinoma There are several predisposing factors for squamous cell carcinoma (SCC): • • • • • • • Actinic damage: squamous carcinomas can also develop in just sun-damaged skin (in the absence of actinic keratosis) X-irradiation Chronic scarring or inflammation Smoking (particularly lesions of the lip) Arsenic ingestion Organic hydrocarbons Immunosuppression • Human papillomavirus. Management of SCC Surgical management is the treatment of choice. Other treatments include radiotherapy, Mohs’ surgery and cryosurgery. Keratoacanthoma Keratoacanthoma is a rapidly growing tumour that arises in sun-damaged skin. It is now considered to be a low-grade SCC and often cannot be reliably distinguished from SCC. Treatment is usually surgical 3.11.4 Other skin tumours CutaneousT-cell lymphoma Cutaneous lymphoma may be T-cell type or B-cell type. Approximately two-thirds of primary cutaneous lymphoma are of T-cell origin. Mycosis fungoides is the most common form (72%). It has several clinical variants and tends to have an indolent course. It may progress over years, from patch stage to plaque stage, and then to tumour stage. Sézary syndrome occurs in 5% of cases and patients have advanced disease with erythroderma, and nodal and blood involvement. Patients have a median survival of <5 years. 3.12 HAIR AND NAILS 3.12.1 Disorders of hair The first signs of hair follicles appear in the region of the eyebrows, upper lip and chin at around 9 weeks’ gestation. By 22 weeks the full complement of follicles is established. Hair abnormalities comprise either excessive hair growth or hair loss. Excessive hair growth can be androgen-independent ‘hypertrichosis’ or androgen-dependent ‘hirsutism’. Causes of hypertrichosis • • Congenital/hereditary • Congenital hypertrichosis lanuginosa • Porphyrias • Epidermolysis bullosa • Hurler syndrome Acquired • Acquired hypertrichosis lanuginosa • • • Endocrine • Hypothyroidism • Hyperthyroidism Drugs • Diazoxide • Minoxidil • Ciclosporin • Streptomycin Other • Malnutrition • Anorexia nervosa Causes of hirsutism • • • Ovarian • Polycystic ovary syndrome • Ovarian tumours Androgen therapy Adrenal • Congenital adrenal hyperplasia • Cushing syndrome • Prolactinoma Loss of hair is called alopecia and can be scarring or non-scarring. Scarring alopecia is loss of hair with destruction of the hair follicles. Non-scarring alopecia is when the hair follicles are preserved. A good example of this is the ‘exclamation mark’ hair seen in alopecia areata. Causes of scarring alopecia • • • • Hereditary • Ichthyosis Bacterial • Tuberculosis • Syphilis Physical injury • Burns • Radiotherapy Fungal • • Kerion Others • Lichen planus • Lupus erythematosus • Morphoea • Sarcoidosis • Cicatricial pemphigoid Causes of non-scarring alopecia • • • • • • Male pattern/androgenic alopecia (the most common in men and women) Alopecia areata Endocrine • Hypopituitary state • Hypothyroidism • Hyperthyroidism • Hypoparathyroidism • Pregnancy Drugs • Retinoids • Anticoagulants • Anti-mitotic agents • Oral contraceptive pill • Carbimazole • Thiouracil • Lithium Iron deficiency Chronic illness Alopecia areata is associated with nail dystrophy, cataracts, vitiligo, autoimmune thyroid disease, pernicious anaemia and Addison’s disease. 3.12.2 Disorders of nails Nails are derived from keratin. This is a protein complex and gives the nail its hard property. The nail can be affected in a variety of skin and systemic disorders. Causes of nail changes associated with skin disorders • • • • • • Psoriasis: nail changes include onycholysis, nail pitting, hyperkeratosis, pustule and occasional loss of nail Fungal: signs include discoloration, onycholysis and thickening of the nail Bacterial: usually due to staphylococcal infections. Pseudomonas infections give a green discoloration to the nail Lichen planus: nail changes occur in 10% of cases, with thinning of the nail plate and longitudinal linear depressions. Occasionally there is destruction of the nail (pterygium) Alopecia areata: pitting, thickening and ridging of the nail (sandpaper nail) are seen Dermatitis: coarse pits, cross-ridging and onycholysis may be seen. Causes of nail changes associated with systemic disease • • • • • Koilonychia: the nails are thin, brittle and concave. There is an association with iron-deficiency anaemia Yellow nail syndrome: the nails are yellow and excessively curved. Associations include recurrent pleural effusions, chronic bronchitis, bronchiectasis, nephrotic syndrome and hypothyroidism Nail–patella syndrome: loss of ulnar half of the nails, usually the thumbnail, is seen. Associations include small patellae, bony spines over posterior iliac crests, renal abnormalities, over extension of joints and laxity of the skin Beau’s lines: these are transverse depressions in the nail due to temporary arrest in growth. They usually occur after a period of illness or infection Half-and-half nails: the proximal nail bed is white and distal, pink or brown. They are associated with chronic renal failure and rheumatoid arthritis. Causes of onycholysis (lifting of the nail plate from the nail bed) • • • • Idiopathic: excessive manicuring or wetting Dermatological disease: psoriasis, fungal infection, dermatitis Systemic disease: impaired peripheral circulation, hypothyroidism, hyperthyroidism Trauma. Chapter 4 Endocrinology CONTENTS 4.1 Hormone action 4.1.1 Types of hormone 4.1.2 Hormones that act at the cell surface 4.1.3 Hormones that act intracellularly 4.1.4 Hormone resistance syndromes 4.2 Specific hormone physiology 4.2.1 Hormones in illness 4.2.2 Hormone changes in obesity 4.2.3 Hormones in pregnancy 4.2.4 Investigations in endocrinology 4.2.5 Growth hormone 4.2.6 Prolactin 4.2.7 Adrenal steroids 4.2.8 Thyroid hormone metabolism 4.2.9 Renin–angiotensin–aldosterone 4.2.10 Calcium, PTH and vitamin D 4.2.11 Atrial natriuretic peptide 4.3 The pituitary gland 4.3.1 Anatomy 4.3.2 Pituitary tumours 4.3.3 Diabetes insipidus 4.3.4 Acromegaly 4.3.5 Prolactinomas 4.3.6 Hypopituitarism and growth hormone deficiency in adults 4.4 Hyponatraemia and SIADH 4.5 The thyroid gland 4.5.1 4.5.2 4.5.3 4.5.4 4.5.5 4.5.6 Hyperthyroidism and hypothyroidism Causes of thyrotoxicosis Thyroid cancer and nodules Drugs and the thyroid Autoimmunity and eye signs in thyroid disease Thyroid function tests 4.6 Adrenal disease and hirsutism 4.6.1 Cushing syndrome 4.6.2 Primary hyperaldosteronism 4.6.3 Congenital adrenal hyperplasia 4.6.4 Hypoadrenalism 4.6.5 Polycystic ovary syndrome and hirsutism 4.7 Phaeochromocytoma and multiple endocrine neoplasia syndromes 4.8 Puberty/growth/intersex 4.8.1 Normal puberty 4.8.2 Precocious puberty 4.8.3 Delayed puberty/short stature 4.8.4 Intersex 4.9 Diabetes mellitus 4.9.1 Risk factors and clinical features of types 1 and 2 diabetes mellitus 4.9.2 Diagnostic criteria for diabetes 4.9.3 Treatment of type 1 diabetes 4.9.4 Treatment of type 2 diabetes 4.9.5 Glycated HbA1c 4.9.6 Microvascular and macrovascular complications of diabetes 4.9.7 Autonomic neuropathy 4.10 Hypoglycaemia 4.10.1 Hypoglycaemia in diabetes mellitus 4.10.2 Hypoglycaemia unrelated to diabetes Endocrinology 4.1 HORMONE ACTION There are three main types of hormone: • amine • steroid • peptide. Knowing which category a particular hormone fits into makes it possible to guess much of its physiology. Thyroxine is an exception to this, as shown below. 4.1.1 Types of hormone • Amine: catecholamines, serotonin, thyroxine • Steroid: cortisol, aldosterone, androgens, oestrogens, progestogens and vitamin D • Peptide: everything else! (made up of a series of amino acids). Thyroxine is chemically an amine but it acts like a steroid. Vitamin D has the structure of a steroid hormone and it acts like one. Amines/peptides • • • • Short half-life (minutes) Secretion may be pulsatile Act on a cell surface receptor Often act via a second messenger Steroids • Longer biological half-life (hours) • Act on an intracellular receptor • Act on DNA to alter gene expression This information can be used to predict hormone action, eg aldosterone is a steroid hormone so it must have a biological half-life of several hours, bind to an intracellular receptor and affect gene transcription. Glucagon is not a steroid or an amine so it must be a polypeptide hormone, which has a short circulation half-life, acts via a cell surface receptor and probably utilises a second messenger (adenosine cyclic monophosphate, or cAMP, in fact). 4.1.2 Hormones that act at the cell surface Peptide and amine hormones act at the cell surface via specific membrane receptors. The signal is transmitted intracellularly by one of three mechanisms: • Via cAMP • Via a rise in intracellular calcium • Via receptor tyrosine kinases. If in doubt, assume the action of a peptide or amine hormone (excluding thyroxine) is via cAMP, unless it is insulin or has the word ‘growth’ in its name, in which case it is likely to act via a receptor tyrosine kinase (Table 4.1). Cyclic AMP and G-proteins Hormone receptors linked to cAMP (eg thyroid-stimulating hormone [TSH] receptor) typically have seven transmembrane domains. The receptor does not directly generate cAMP but acts via separate ‘G-proteins’ on the cell surface which, in turn, interact with the cAMP-generating enzyme, adenylyl cyclase, on the cell surface. (See Figure 14.4 in Chapter 14, Molecular Medicine.) Hormones that raise the level of cAMP intracellularly (all hormones in this category except somatostatin) act via a stimulatory G-protein, ‘Gs’. Hormones that lower the level of cAMP (somatostatin) act via an inhibitory G-protein, ‘Gi’. Table 4.1 Mechanisms of hormone action Via cAMP Via Ca2+ Via receptor tyrosine kinases Adrenaline (β receptors) GnRH Insulin All pituitary hormones except GH, PRL TRH GH, PRL Adrenaline (α Glucagon ‘Growth factors’: IGF-1, EGF receptors) Somatostatin cAMP, adenosine cyclic monophosphate; EGF, epidermal growth factor; GH, growth hormone; GnRH, gonadotrophin-releasing hormone; IGF-1, insulin-like growth factor 1; PRL, prolactin; TRH, thyrotrophin-releasing hormone. G-proteins are important in endocrinology because mutations in Gs have been found to be associated with certain diseases: Acromegaly: 40% of patients with acromegaly have an activating somatic mutation of Gs in their • pituitary tumour. As a result, the cells are always ‘switched on’ and continuously make growth hormone (GH), resulting in acromegaly McCune–Albright syndrome: an activating mutation of Gs early in embryonic development causes hyperfunction of one or more endocrine glands with the following sequelae: precocious puberty (gonad hyperfunction), acromegaly (GH hypersecretion), Cushing syndrome (adrenal • gland hyperfunction), thyrotoxicosis or hyperparathyroidism. The syndrome is associated with café-au-lait spots and polyostotic fibrous dysplasia. As the mutation occurs after the zygote stage, affected individuals are a mosaic and different patterns of tissue involvement may be seen between individuals Pseudohypoparathyroidism: inactivating germline mutations in Gs result in pseudohypoparathyroidism type 1A if maternally inherited, with dysmorphic features (including short fourth or fifth metacarpal) and resistance to a variety of hormones that act via cAMP (including parathyroid hormone, TSH and gonadotrophins). Spontaneously occurring or • paternally inherited mutations cause the dysmorphic features alone (pseudopseudohypoparathyroidism). The dysmorphic bone features are sometimes referred to as ‘Albright’s hereditary osteodystrophy’ and can be present in either the maternally or the paternally inherited form. Intracellular Ca2+ Some hormones release intracellular Ca2+ as a second messenger (see Table 4.1 for examples). The receptors for these hormones activate different G-proteins (eg Gq), which in turn activate the cytoplasmic enzyme phospholipase C (PLC). PLC releases the small molecule inositol-1,4,5triphosphate (IP3) from membrane phospholipids. IP3 in turn binds to the IP3-sensitive receptor on the endoplasmic reticulum within the cell, causing Ca2+ to be released from stores in the endoplasmic reticulum into the cytoplasm. The Ca2+ subsequently affects cell metabolism by binding to the protein calmodulin. Receptor tyrosine kinases The insulin, GH, prolactin and growth factor receptors do not use second messengers. The receptors themselves can act as enzymes that phosphorylate (‘kinase activity’) other proteins when hormone is bound at the cell surface. This is followed by a cascade of proteins phosphorylating other proteins until gene transcription in the nucleus is modulated. 4.1.3 Hormones that act intracellularly Steroids, vitamin D and thyroxine are sufficiently lipid-soluble that they do not need cell surface receptors but can diffuse directly through the cell membrane. They then bind to receptors in the cytoplasm, which results in shedding of heat shock proteins that protect the empty receptor. The hormone–receptor complex migrates into the nucleus where it alters the transcription of a large number of genes (see Figure 14.6 in Chapter 14, Molecular Medicine). 4.1.4 Hormone resistance syndromes The following are conditions of hormone resistance with the site of the defect shown. • Receptor defect (hormone involved) • Laron’s dwarfism (GH) • Leprechaunism (Donahue’s syndrome, Rabson–Mendenhall syndrome [insulin]) • Nephrogenic diabetes insipidus (antidiuretic hormone [ADH]) • Androgen resistance (testicular feminisation syndrome (testosterone)) • Vitamin-D-dependent rickets type 2 – hereditary vitamin D resistance rickets (vitamin D)a • Second messenger defect • Pseudohypoparathyroidism • Defect unknown • Type 2 diabetes aVitamin D-dependent rickets type 1 is due to a failure of 1-hydroxylation of vitamin D. 4.2 SPECIFIC HORMONE PHYSIOLOGY 4.2.1 Hormones in illness During illness/stress, the body closes all unnecessary systems down ‘from the top’, eg the thyroid axis closes down by a fall in thyrotrophin-releasing hormone (TRH), TSH and L-thyroxine/Ltriiodothyronine (T4/T3). It is orchestrated by the hypothalamus, not by the end-organs. Hormones involved in the stress response may rise. Hormones that fall • • • • TSH, T4/T3a LH, FSH Testosterone, oestrogen Insulin (starvation) May rise (stress hormones) • • • • GH (though IGF-1 falls) ACTH, glucocorticoids Adrenaline Glucagon (starvation) • Prolactin aIn this case conversion of T4 to T3 is inhibited so T3 falls more than T4 ACTH, adrenocorticotrophic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; IGF-1, insulin-like growth factor 1; LH, luteinising hormone; T3, L-triiodothyronine; T4, L-thyroxine; TSH, thyroid-stimulating hormone. In starvation alone, without illness, all hormones fall except glucagon. In anorexia nervosa there is also stress: all hormones fall except glucagon, GH and glucocorticoids. 4.2.2 Hormone changes in obesity In the absence of other diseases (eg type 2 diabetes), which might develop in obese patients, the following changes are seen in obesity: • • • • • Hyperinsulinaemia Increased cortisol turnover but not hypercortisolism Increased androgen levels in women Reduced GH Conversion of androgens to oestrogens A proatherogenic lipid profile develops (low high-density lipoprotein [HDL], high low-density • lipoprotein [LDL] and triglyceride). Leptin, adipokines and other hormones involved with appetite and weight Leptin was identified as a product of the ‘ob’ gene in 1994. Ob/ob mice make no leptin, owing to a homozygous ob gene mutation, and are grossly obese. • • • • • • Leptin is a polypeptide hormone, released from fat cells, that acts on specific receptors in the hypothalamus to reduce appetite Circulating leptin levels are directly proportional to fat mass, and so they tell the brain how fat an individual is Leptin appears to have stimulatory effects on metabolic rate and levels fall in starvation (appropriate change for weight homeostasis) Adequate leptin levels are required for the onset of puberty Persistently obese individuals appear relatively resistant to leptin Congenital leptin deficiency presents in childhood with gross obesity and hyperphagia. This changes dramatically with treatment of exogenous leptin. Several other hormones have recently been shown to affect appetite and weight: Ghrelin: this was first identified as a GH-releasing hormone. It is released from the stomach when subjects are fasting or in conditions of negative energy balance and triggers hunger. It • stimulates gastric contraction and hence gastric emptying. Ghrelin levels fall after gastric bypass surgery, which may help weight loss by reducing appetite Peptide YY (a member of the neuropeptide Y family): released from L cells in the small and • large bowel. Levels rise after meals and reduce appetite. This may be the main regulator of dayto-day appetite Glucagon-like peptide-1 (GLP-1): also released from L cells of the intestine after meals and powerfully promotes insulin secretion in response to raised glucose (‘incretin effect’), as well as • possibly reducing appetite. Inactivated by the enzyme dipeptidylpeptidase-4 (DPP-4). Derived from tissue-specific cleavage of proglucagon Oxyntomodulin: also released from L cells and derived from proglucagon; appears to act on the • same receptor as GLP-1, but with less incretin, and has more of an appetite-suppressing effect Neuropeptide Y (NPY), from the hypothalamus itself, and Agouti-related protein (AgRP) • increase appetite, whereasα-melanocyte-stimulating hormone (α-MSH, a melanocortin) reduces appetite. In addition to leptin, a number of other hormones have recently been identified as being released from fat cells. These ‘adipokines’ include adiponectin, which reduces insulin resistance, and resistin and acylation-stimulating protein (ASP), which both increase insulin resistance. Visfatin (also known as nicotinamide phosphoribosyltransferase [NAMPT] and pre-B-cell colony-enhancing factor) is released predominantly from visceral fat and has insulin-like actions. The role of these adipokines in the association between obesity and insulin resistance remains uncertain. 4.2.3 Hormones in pregnancy As a general rule, most hormone levels rise in pregnancy. Insulin resistance develops, causing a rise in circulating insulin levels. Insulin requirements are highest in the last trimester but fall slightly in the last 4 weeks of pregnancy. Other key features of hormone metabolism in pregnancy are as follows: Prolactin levels rise steadily throughout pregnancy and, in combination with oestrogen, prepare the breast for lactation. Post-partum surges of prolactin and oxytocin are generated by the nipple • stimulation of breastfeeding. However, after several weeks, prolactin levels fall almost to normal, even if breastfeeding continues LH/FSH from the pituitary are no longer necessary after conception for continued pregnancy • (although the pituitary may double in size) and the placenta takes over Thyroid axis: thyroid-binding globulin (TBG) levels rise in the first trimester, causing a rise in total T4 and total T3. However, human chorionic gonadotrophin (hCG) from the placenta shares its α subunit with TSH, and very high levels in the first trimester can cause true mild • thyrotoxicosis (not just a binding protein rise), especially associated with hyperemesis gravidarum. Note that T4 and T3 do not cross the placenta very efficiently, but sufficient T4 does cross to prevent a fetus with congenital hypothyroidism becoming hypothyroid until after birth. 4.2.4 Investigations in endocrinology The plasma level of almost all hormones varies through the day (because of pulsatile secretion, environmental stress or circadian rhythms) and is influenced by the prevailing values of the substrates that they control. This makes it hard to define a ‘normal range’, eg insulin values depend on the glucose level, and GH levels depend on whether a pulse of GH has just been released or the blood sample is taken in the trough between pulses. Dynamic testing is therefore frequently used, ie suppression or stimulation tests. The principle is, ‘If you think a hormone level may be high, suppress it; if you think it may be low, stimulate it’. Suppression tests are used to test for hormone EXCESS, eg dexamethasone suppression for Cushing syndrome, glucose tolerance for GH in acromegaly Stimulation tests are used to test for hormone DEFICIENCY, eg Synacthen tests for • hypoadrenalism, insulin-induced hypoglycaemia for GH deficiency and/or hypoadrenalism. • 4.2.5 Growth hormone This is secreted in pulses lasting 30–45 minutes separated by periods when secretion is undetectable. The majority of GH pulses occur at night (‘children grow at night’). In response to GH pulses, the liver makes insulin-like growth factor 1 (IGF-1, previously called somatomedin C), the plasma level of which is constant and which mediates almost all the actions of GH, ie GH does not act directly. The effective levels of IGF-1 are influenced by changes in the level of its six binding proteins (IGFBP 1–6). 4.2.6 Prolactin Prolactin causes galactorrhoea but not gynaecomastia (oestrogen does this). Raised prolactin levels are essentially the only cause of galactorrhoea, although occasionally prolactin levels in the normal range can cause milk production in a sensitised breast. Raised prolactin levels also ‘shut down’ the gonadal axis ‘from the top’ (hypothalamic level), resulting in low GnRH, LH and oestrogen/testosterone levels. Surprisingly, prolactin is a stress hormone and can rise in various levels of stress, from anxiety about venepuncture to an epileptic fit. Prolactin release from the pituitary is under negative control by dopamine from the hypothalamus. Oestrogens (the pill, pregnancy) and nipple stimulation raise prolactin. Prolactin is raised by • • • • • • • • Phenothiazines, haloperidol (not tricyclics) Antiemetics (eg metoclopramide) Damage to hypothalamus (eg radiation) Pregnancy Nipple stimulation Damage to pituitary stalk (eg pressure from a pituitary tumour) Oestrogens Polycystic ovary syndrome Prolactin is suppressed by • Dopamine agonist drugs (eg bromocriptine, cabergoline) Gynaecomastia This is due to a decreased androgen:oestrogen ratio in men. Gynaecomastia is unrelated to galactorrhoea (which is always due to prolactin). Breast enlargement is not necessary to make milk. Causes of gynaecomastia: • • • • • • Pubertal (normal) Obesity – not true gynaecomastia Hypogonadism (eg Klinefelter’s syndrome, testicular failure) Cirrhosis, alcohol Hyperthyroidism Drugs: including spironolactone, digoxin, oestrogens, cimetidine, anabolic steroids, marijuana Tumours, including adrenal or testicular, making oestrogen; lung, pancreatic, gastric, making • hCG; hepatomas converting androgens to oestrogens. 4.2.7 Adrenal steroids These act intracellularly to alter the transcription of DNA to mRNA (see Section 4.1, Hormone action). Surprisingly, the mineralocorticoid (aldosterone) and glucocorticoid receptors have an equal affinity for cortisol. However, the cellular enzyme 11-β-hydroxysteroid dehydrogenase ‘protects’ the mineralocorticoid receptor by chemically modifying any cortisol that comes near the receptor to an inactive form, while having no effect on aldosterone itself. Inactivating mutations of this enzyme, or inhibition of it by liquorice, causes ‘apparent mineralocorticoid excess’, because cortisol (which circulates at much higher concentrations than aldosterone) is able to stimulate the mineralocorticoid receptor. The effects of adrenal steroids and their duration of action are given in Table 4.2. Table 4.2 Adrenal steroids Cortisol = hydrocortisone Prednisolone Dexamethasone Fludrocortisone Relative glucocorticoid effect Relative mineralocorticoid effect Duration of action 1 + Short 4 30 10 ± − +++ Medium Long 4.2.8 Thyroid hormone metabolism More than 95% of thyroid hormones are bound to plasma proteins in the circulation, predominantly TBG and thyroid-binding prealbumin (TBPA). T4 (four iodine atoms per molecule) has a half-life of 7 days (so, if a patient is in a confused state, it is possible to administer his or her total weekly dose of thyroxine once a week). It is converted partly in the thyroid and partly in the circulation to T3 (three iodine atoms per molecule), which is the active form and has a half-life of 1 day. There are three deiodinase enzymes that act on thyroid hormones (D1–D3). D1 and D2 promote the generation of active hormone (T3) by converting T4 to T3 (Figure 4.1). D3 opposes this by promoting conversion of T4 to reverse T3 (rT3) and destroying T3 by conversion to T2 (inactive). The D1 and D2 enzymes are inhibited by illness, propranolol, propylthiouracil, amiodarone and ipodate (formerly used as X-ray contrast medium for study of gallbladder disease). This reduces the level of active hormone, T3, with little change or a rise in T4. Reverse T3 levels rise (T4 spontaneously converts to rT3 if the monodeiodinase is not available), but rT3 is not detected in laboratory tests of T3 levels. Figure 4.1 Metabolism of thyroid hormones, D1–D3, different deiodinase enzymes that act on thyroid hormone. It is said that you should ‘never measure thyroid function tests on the intensive care unit because you will not be able to interpret them’. In illness, TSH and free T3 levels fall (‘sick euthyroidism’). The only interpretable finding in sick patients is a raised free T3 – this would almost definitely indicate thyrotoxicosis. 4.2.9 Renin–angiotensin–aldosterone Aldosterone secretion is controlled almost completely by the renin–angiotensin system, not by ACTH. The initial letters of the zones of the adrenal cortex from outside inwards spell ‘GFR’, similar to glomerular filtration rate: glomerularis, fasciculata, reticularis. Aldosterone is the ‘outsider hormone’ and is made on the ‘outside’ (zona glomerulosa). Renin is released from the JGA (juxtaglomerular apparatus) of the kidney in response to low Na+ delivery or reduced renal perfusion. Renin is an enzyme that converts angiotensinogen to angiotensin I (10 amino acids). ACE (angiotensin-converting enzyme) in the lung converts angiotensin I to angiotensin II, which is the active form. ACE also breaks down bradykinin: ACE inhibitors (eg captopril) are believed to cause cough as a result of a build-up of bradykinin in the lung. The renin– angiotensin system is designed to restore circulating volume. It is therefore activated by hypovolaemia (Figure 4.2) and its end product, angiotensin II, has three actions that restore volume: • Releasing aldosterone from the adrenal (retains Na+, excretes K+ in the distal tubule) • Vasoconstriction (powerful) • Induction of thirst (powerful). 4.2.10 Calcium, PTH and vitamin D (See also Chapter 13, Metabolic Diseases.) Figure 4.2 The renin–angiotensin system. Plasma calcium is tightly regulated by parathyroid hormone (PTH) and vitamin D, acting on the kidney (PTH), bone (PTH) and gut (vitamin D). PTH controls Ca2+ levels minute to minute by mobilising Ca2+ from bone and inhibiting Ca2+ excretion from the kidney. Vitamin D has a more long-term role, predominantly by promoting Ca2+ absorption from the gut. Its actions on the kidney and bone are of lesser importance. Ca2+ levels are sensed by a specific calcium-sensing receptor on the parathyroid glands. Mutations that reduce the activity of this receptor result in a resetting of calcium and PTH to higher levels (familial hypocalciuric hypercalcaemia, FHH). Activating mutations can also occur, which result in a picture almost indistinguishable from hypoparathyroidism, with a low Ca2+ (autosomal dominant hypocalcaemia with hypercalciuria). It is important to identify these conditions because they run a benign course and only attempted treatment causes problems (eg raising the serum Ca2+ in autosomal dominant hypocalcaemia will predispose to renal stone formation). Precursor vitamin D, obtained from the diet or synthesised by the action of sunlight on the skin, requires activation by two steps: • 25-hydroxylation in the liver • 1-hydroxylation in the kidney. PTH can promote 1-hydroxylation of vitamin D in the kidney, ie it can activate vitamin D, thereby indirectly stimulating Ca2+ absorption from the gut. Calcitonin (from the C cells of the thyroid) behaves almost exactly as a counter-hormone to PTH (secreted by high Ca2+, acts to lower serum Ca2+ by inhibiting Ca2+ release from bone), but its physiological importance is in doubt (thyroidectomy does not affect Ca2+ levels if the parathyroid glands are undisturbed). 4.2.11 Atrial natriuretic peptide Atrial natriuretic peptide (ANP) physiology can be predicted from its name: • Atrial: it is synthesised by the myocytes of the right atrium and ventricle Natriuretic: it causes a natriuresis (urinary excretion of sodium). It thereby reduces circulating volume (opposite of renin–angiotensin). As you would predict, therefore, it is secreted in • conditions of hypervolaemia – via stretch of the right atrial and ventricular walls. It also antagonises the other actions of angiotensin II by causing vasodilatation and reduced thirst/salt craving • Peptide: it is a peptide hormone (which acts via cAMP). There are two other natriuretic peptides, B-type and C-type natriuretic peptides (BNP and CNP). BNP is similar to ANP, and is produced from the heart, especially in heart failure. Serum levels are more stable than those of ANP, and BNP is proving to be a useful test of heart failure. CNP is produced by the vascular endothelium rather than cardiac myocytes. 4.3 THE PITUITARY GLAND 4.3.1 Anatomy The anatomical relations of the pituitary (Figure 4.3) are important because enlarging pituitary tumours may press on surrounding structures. Above: optic chiasma (classically causing bitemporal hemianopia if compressed, but any visual field defect may occur), pituitary stalk, hypothalamus, temporal lobes • Below: sphenoid sinus (in front and below to allow trans-sphenoidal surgery), nasopharynx • Lateral: cavernous sinus, internal carotid arteries, III, IV, V, and V and VI cranial nerves. • Expanding pituitary tumours may also compromise remaining anterior pituitary function, but rarely affect posterior pituitary hormones. 4.3.2 Pituitary tumours A microadenoma is a pituitary tumour <10 mm in size. The size and frequency of pituitary tumours are related. Figure 4.3 Schematic sagittal section through the pituitary to show its relation to surrounding structures. Pituitary tumours • Large – non-secreting (typically chromophobe): 50% of all tumours • Large – prolactinomas in men: 25% of all tumours • Medium – acromegaly (typically ‘acidophil’, 70% are about 1 cm): 12% of all tumours Small – Cushing’s disease (often undetectable on CT/MRI, typically basophil): 5–10% of all • tumours • Small – TSH secreting: 1% (very rare) The most common tumours are small, nonfunctioning microadenomas, which have been reported to occur in up to 20% of people post mortem. Prolactinomas are the most common functioning pituitary tumours. Microprolactinomas are more frequent than macroprolactinomas. True Cushing’s disease is used to describe pituitary-dependent Cushing syndrome. This is caused by excessive ACTH production from the pituitary gland (usually by a microadenoma). They are in themselves rare. For further discussion about Cushing syndrome diagnosis and management, please see Section 4.6.1. Excessive secretion of GH from the pituitary gland in adults is termed ‘acromegaly’. There is a preponderance to macroadenomas with blunting of the normal pulsatile GH secretion. Pituitary apoplexy is sudden enlargement of the pituitary by haemorrhage into a tumour, typically causing the combination of headache, neck stiffness and sudden blindness associated with cardiovascular collapse due to hypopituitarism. Treatment is with steroid replacement and urgent surgery for visual loss (to decompress optic chiasma). In pituitary failure the only two hormones that must be replaced for survival are T4 and hydrocortisone. It is important to ensure that the patient is adequately replaced with glucocorticoids before starting replacement of T4, because levothyroxine increases glucocorticoid clearance. Craniopharyngiomas are benign tumours that arise from remnants of Rathke’s pouch. Two-thirds arise in the hypothalamus itself (suprasellar) and a third in the sella. They are usually cystic, frequently calcify, often recur after aspiration and, although they represent an embryonic remnant, they not infrequently present in adulthood. 4.3.3 Diabetes insipidus ADH (also called vasopressin or arginine–vasopressin, AVP) is synthesised in the hypothalamus and transported to the posterior pituitary, along with oxytocin, for storage and release. Diabetes insipidus (DI) is caused either by a failure to secrete vasopressin from the posterior pituitary (central or cranial DI) or resistance to the action of vasopressin in the kidney (nephrogenic DI). To cause cranial DI, the hypothalamic nuclei (supraoptic and paraventricular) need to be damaged – it is not sufficient simply to compress the posterior pituitary, because vasopressin can be secreted directly from the hypothalamus itself. Pituitary tumours therefore rarely cause Dl. Major causes of cranial diabetes insipidus • • • • • • • Idiopathic Craniopharyngiomas Infiltrative processes of the hypothalamus (eg sarcoid, histiocytosis X) Trauma Pituitary surgery Lymphocytic hypophysitis Dysgerminomas Causes of nephrogenic DI Reduced action of ADH on the kidney can have several causes: • Primary • Childhood onset: X-linked/dominant abnormality in tubular ADH receptor • Secondary (common) • Hypercalcaemia • Hypokalaemia • Renal disease (particularly if it involves the medullary interstitium) • Lithium • Demeclocycline Water deprivation test A water deprivation test (Table 4.3) is used to identify the cause of polydipsia and/or polyuria. It is worth confirming polyuria (urine output >3000 mL/24 h) before proceeding to a water deprivation test. Major metabolic causes should first be excluded (eg hyperglycaemia, hypercalcaemia, hypokalaemia, chronic renal failure). The patient is then deprived of water (from the night before if polyuria is not excessive) and hourly urine and plasma osmolality are measured until 3% of the body weight is lost. The patient is then given an injection of DDAVP (a synthetic analogue of ADH). Interpretation of the water deprivation test Primary polydipsia (compulsive water drinking): in this condition the patient is not dehydrated but water overloaded in the resting state (Na+ <140 mmol/l). Chronic polydipsia in this • condition can result in washout of the renal medullary-concentrating gradient so that, even if the patient does become dehydrated, with a rise in ADH, urine cannot be concentrated Table 4.3 Interpretation of the water deprivation test Initial plasma osmolality Normal Normal Cranial Dl High Nephrogenic Dl High Primary polydipsia Low Partial cranial Dl High Final urine osmolality (mosmol/kg) Urine osmolality post-DDAVP (mosmol/kg) >600 >600 <300 >600 <300 <300 300–400 (approx.) 400 (approx.) 300–400 400–600 Final plasma ADH High Low High Moderate Relatively low ADH, antidiuretic hormone; Dl, diabetes insipidus. Cranial Dl: in this condition there is failure to concentrate urine due to lack of ADH. This is observed with a high plasma osmolality and a relatively low urine osmolality throughout the test. Administration of DDAVP allows the kidneys to concentrate urine, thus raising the osmolality. If • the thirst mechanism is intact, patients attempt to compensate by increasing their fluid intake orally. If, however, this mechanism is disrupted (patient is unconscious or has intracerebral lesion rendering the patient adipsic), there is a significant risk of becoming dehydrated very quickly Partial cranial Dl: in this condition there is weak ADH production. There is a similar effect on • the renal medullary-concentrating gradient to that seen in primary polydipsia, and so the two conditions cannot be differentiated unless a post-hydration serum ADH level is obtained Nephrogenic diabetes inspidus: despite adequate circulating ADH, there is renal resistance to the action of ADH, resulting in an inability to concentrate urine. Therefore urine osmolality does • not improve on administration of DDVAP during the water deprivation test. Treatment is by correcting the underlying cause and ensuring adequate hydration. Sometimes high doses of DDAVP can be used. 4.3.4 Acromegaly The common features of acromegaly are well known (hand and foot enlargement, coarse facial features, overbite of the lower jaw, splaying of the teeth) but the following also occur (see box). Features of acromegaly • • • • • • • • • • • • • • • Diabetes Arthropathy – often pseudogout Sleep apnoea Carpal tunnel syndrome Multinodular goitre Increase in malignancies, especially colonic polyps Hypertension Twofold increase in death from cardiovascular disease Cardiomyopathy Left ventricular hypertrophy Enlarged testes Renal stones (hypercalciuria) Raised phosphate Raised prolactin, galactorrhoea, menstrual change Raised triglycerides Acromegaly is almost always due to a GH-secreting pituitary tumour. Rarely, the condition is due to ectopic GH-releasing hormone (GHRH) secretion from a tumour (typically carcinoid) which stimulates the normal pituitary (no discrete tumour seen on MRI). Biochemical tests usually reveal a raised serum IGF-1 level (above the age- and gender-specific normal range). The diagnosis is confirmed by failure to suppress GH to a nadir of 0.4 ng/mL on an oral glucose tolerance test. First-line treatment is trans-sphenoidal surgery to resect the pituitary tumour (or transcranial surgery if there is a large suprasellar extension of the tumour). The cure rate is very variable (40–80%), and is dependent on the extent of lateral and superior extension and the skill of the surgeon. Alternative therapies are dopamine agonists (bromocriptine, cabergoline, quinagolide, pergolide, which reduce GH secretion in approximately 20% of cases), somatostatin analogues (octreotide, which inhibit GH secretion), GH antagonists (pegvisamant, which blocks GH) and pituitary radiotherapy (may take years to take effect and may result in hypopituitarism). After successful treatment of acromegaly most physical features do not regress, although some soft-tissue effects do. Features of active disease are increased sweating and oedema, together with evidence of metabolic effects such as poor glycaemic and hypertensive control. 4.3.5 Prolactinomas Prolactinomas are the most common functioning pituitary tumours. They present with galactorrhoea, gonadal dysfunction (amenorrhea, oligomenorrhoea, poor libido, erectile dysfunction, subfertility) and symptoms of mass effect (headache and deterioration in visual fields). Diagnosis is based on raised serum prolactin concentrations and demonstration of a pituitary lesion on MRI. Microadenomas can be hard to detect on imaging and may appear as gland asymmetry, but generally speaking the size of the lesion is proportional to the prolactin level. Treatment is aimed at normalising the prolactin level, restoring gonadal function and reducing the size of the lesion. The first-line treatment of prolactinomas is medical management. Dopamine agonists such as cabergoline and bromocriptine suppress prolactin levels to normal in approximately 95% of cases, with shrinkage of the tumour in about 85%. Surgery is usually reserved for patients who are intolerant or resistant to dopamine agonists. 4.3.6 Hypopituitarism and growth hormone deficiency in adults Panhypopituitarism can be caused by enlarging pituitary tumours, cranial irradiation (including specific pituitary radiotherapy), pituitary apoplexy, Sheehan’s syndrome (infarction after post-partum haemorrhage), and then by any of the conditions that can cause cranial diabetes insipidus (see box on p. 118). Patients present with a soft, smooth ‘baby’ skin, ‘crows’ feet’ lines around the eyes and features related to their specific hormonal deficiencies – hypotension in relation to ACTH deficiency, weight gain in relation to TSH deficiency, etc. Typically, hormone loss follows a common pattern, with GH deficiency being most common, followed in order by LH, FSH, ACTH and TSH deficiency. Secondary hypothyroidism is suggested by a low free T4 (fT4) in the context of a low or inappropriately normal TSH. ACTH deficiency is diagnosed by an insulin stress test or glucagon test or, if longstanding, may be suggested by a failed short Synacthen test with low or inappropriately normal ACTH levels, although this test depends on the presence of adrenal atrophy subsequent to ACTH deficiency. The following points should be noted: • Only replacement therapy with corticosteroids and T4 is essential for life In suspected hypopituitarism, the steroids should be given first and certainly before thyroid replacement therapy. This is because correction of hypothyroidism will accelerate cortisol • metabolism and would precipitate a hypoadrenal crisis (if T4 is given before exogenous steroids) If the pituitary is damaged, GH production is lost early, so that most patients are GH-deficient • (see below) Despite conventional hormone replacement therapy (T4, glucocorticoid and sex steroids), • mortality rates are increased in hypopituitarism due to cardiovascular events or malignancy. The potential for GH therapy to reverse this trend is currently undergoing research. GH deficiency The main role for GH in children is growth; however, in adults GH is required for musculoskeletal, metabolic and possibly psychological wellbeing. Adult GHD is associated with the following: • Reduced muscle tone and power, increased fat mass, easy fatigability, poor exercise tolerance • Low mood, poor concentration and memory • Osteoporosis Increased cardiovascular risk (impaired endothelial function, proatherogenic lipid profile, • impaired left ventricular function). Based on guidance of the National Institute for Health and Care Excellence (NICE), GH replacement in adults is indicated for impaired quality of life in patients with severe GH deficiency (defined as a peak GH response <9 mU/L [3 ng/mL] during a stimulation test). These symptoms are reassessed after a 9-month period of treatment. Treatment is with recombinant GH given nightly by subcutaneous injection. Longer-acting preparations are currently under review 4.4 HYPONATRAEMIA AND SIADH ADH (or vasopressin) is synthesised in magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. ADH is released in response to rising plasma osmolality and acts on the distal tubule and renal collecting ducts to increase water permeability. Water is reabsorbed and the urine becomes more concentrated. When the ADH system is working normally, ‘the urine should reflect the blood’, ie concentrated urine should occur when the plasma osmolality is high, and vice versa. However, hypovolaemia is also a strong signal for ADH release, and in the presence of hypovolaemia, ADH will be secreted even if the osmolality is low. This explains the hyponatraemia seen in renal, cardiac and liver failure, as well as after excessive sodium loss (eg diarrhoea). Other stimuli can also commonly override control of ADH secretion by osmolarity (see Syndrome of inappropriate ADH secretion [SIADH] below). Syndrome of inappropriate ADH secretion Many common stimuli override the control of osmolality and cause inappropriate amounts of ADH to be secreted, causing hyponatraemia. Sodium concentration should be high in the urine (excluding hypovolaemia), renal, adrenal and thyroid function should be normal, and diuretic therapy needs to be excluded before SIADH is diagnosed. Treatment is by fluid restriction or, if necessary, oral demeclocycline. Causes of inappropriate secretion of ADH include • • • • Nausea Pain Fits Pneumonia • • • • • • • Other central nervous system/lung insults Smoking Chlorpropamide Carbamazepine Head injury Cerebrovascular accidents (CVAs) Tumours making ectopic ADH (eg bronchus) If a tumour is the cause, it is usually obvious: a search for malignancy beyond a chest radiograph is not required in SIADH. Smoking makes you pass less urine (releases ADH); drinking (alcohol) makes you pass more (inhibits ADH secretion). Causes of hyponatraemia Hyponatraemia can be divided into three categories: • ‘Real’ (low serum osmolality) • Pseudohyponatraemia: high triglycerides, high protein (eg myeloma) (normal serum osmolality) • Dilutional: high glucose, ethanol, mannitol (serum osmolality may be raised). If hyponatraemia is confirmed to be ‘real’ (low plasma osmolality, glucose not raised, and no suggestion of ethanol or mannitol in blood), then the following clinical and laboratory pointers must be considered: • Careful history for drug use (especially diuretics) and of fluid loss (eg diarrhoea) • Examination for circulatory volume status (oedema, postural hypotension and skin turgor) • Measurement of urinary sodium concentration (Table 4.4). Hypoadrenalism is the most important diagnosis not to be missed, because untreated, it can result in death. 4.5 THE THYROID GLAND 4.5.1 Hyperthyroidism and hypothyroidism The common features of hyperthyroidism (eg weight loss, tremor, palpitations) and hypothyroidism (eg weight gain, lethargy, dry skin) are well known but questions are often asked on the more unusual features. ‘Recognised’ features of the two major thyroid syndromes are summarised in Table 4.5. Table 4.4 Causes of hyponatraemia Urine sodium (mmol/L) Hypovolaemia present Features of hyper- and hypothyroidism >20 Diuretics SIADH Hypoadrenalism Salt-losing nephropathy Renal failure Congestive cardiac failure, cirrhosis, nephrotic syndrome Vomiting, diarrhoea <10 Hypothyroidism Loss of other fluid SIADH, syndrome of inappropriate antidiuretic hormone secretion. Features of hyper- and hypothyroidism Amenorrhoea may be associated with hyperthyroidism because of associated weight loss. In hypothyroidism, everything slows down except the periods! The menorrhagia can cause a microcytic anaemia in contrast to the more usual macrocytosis. In both conditions there may be subfertility. In the gastrointestinal tract, the symptoms of hyperthyroidism are almost indistinguishable from those of anxiety. The diarrhoea is actually more like the increased bowel frequency before an examination. Both hyperthyroidism (if Graves’ disease) and hypothyroidism can cause periorbital oedema (see note in Section 4.5.5 on eye signs in thyrotoxicosis) The leukopenia of thyrotoxicosis can be misdiagnosed: thionamide drugs (eg carbimazole) used • as treatment also commonly cause a lymphopenia. Both of these are separate from the agranulocytosis that rarely occurs with thionamide drugs In hyperthyroidism the urticaria due to the disease itself can cause confusion with the • maculopapular rash, which develops in 10% of patients treated with thionamide drugs. • Table 4.5 Features of hyper- and hypothyroidism Features Hyperthyroidism Hypothyroidism General Weight gain (rarely) Gynaecomastia Occult in elderly people Hair loss Weight gain Serous effusions (pleural, pericardial, ascites, joint) Hair loss Gynaecological Raised sex hormone-binding globulin (SHBG) Amenorrhoea, menorrhagia Infertility Gastrointestinal Raised alkaline phosphatase (derived from liver and bone) Vomiting Diarrhoea Constipation Muscle Proximal myopathy Periodic paralysis (especially Chinese) Raised creatine kinase Chest pain (muscular) Muscle cramps Dyspnoea Cardiovascular system Atrial fibrillation with high Hypercholesterolaemia stroke rate High-output cardiac Ischaemic heart disease failure Bone Osteoporosis Hypercalcaemia Neurological ‘Apathetic thyrotoxicosis’ Deafness Ataxia, confusion, coma Eyes Eye signs (see Section 4.5.5) Periorbital oedema Blood Leukopenia Microcytic anaemia Macrocytic anaemia Microcytic, if menorrhagia Skin Urticaria Dry, orange (carotenaemia) Side-effects of anti-thyroid drugs (carbimazole, propylthiouracil) • Common • Rash • Leukopenia • Rare • Agranulocytosis • Aplastic anaemia • Hepatitis • Fever • Arthralgia • Vasculitis (propylthiouracil) (See also Chapter 2, Clinical Pharmacology, Toxicology and Poisoning) 4.5.2 Causes of thyrotoxicosis The three common causes of thyrotoxicosis are: • Graves’ disease • toxic multinodular goitre • toxic (hot) nodule. In all these conditions all or part of the gland is overactive and the gland takes up a normal or increased amount of radioiodine. In the following conditions, there is thyrotoxicosis without increased production of new hormone by the thyroid gland itself, ie radioiodine uptake is suppressed: • Excess thyroxine ingestion • Thyroiditis: post-viral (de Quervain’s), post-partum or silent thyroiditis • Ectopic thyroid tissue, eg lingual thyroid or ovary (struma ovarii) Iodine administration: gland is actually still active, but cold iodine competes with radioiodine • during scanning. 4.5.3 Thyroid cancer and nodules Only 5–10% of thyroid nodules are malignant (the rest are adenomas). Thyroid cancer virtually never causes hyperthyroidism, so ‘hot nodules’ can usually be presumed to be benign. In order of increasing malignancy and decreasing frequency, the thyroid epithelial cancers are: • papillary • follicular • anaplastic. Lymphomas occur in Hashimoto’s disease. Medullary thyroid cancer is from the C cells (calcitonin), not from the thyroid epithelium. Serum calcitonin is a tumour marker for this cancer, which often occurs in families, sometimes as part of the multiple endocrine neoplasia type 2 syndrome (see Section 4.7). 4.5.4 Drugs and the thyroid • Lithium • Inhibits T4 release from the gland, causing hypothyroidism • Oestrogens • Raised TBG and hence ‘total’ T4 /T3 • Amiodarone • Inhibits T4 to T3 conversion, increasing reverse T3 • High iodine content can cause hyper- or hypothyroidisma • Iron – if taken at the same time as thyroxine, can reduce its absorption • Interferon • Induces anti-thyroid autoantibodies and hypothyroidism (usually transient) aNote on amiodarone-induced hyperthyroidism. This may be due to drug-induced damage (thyroiditis) or to the excess iodine in amiodarone, and can be very resistant to treatment. 4.5.5 Autoimmunity and eye signs in thyroid disease In areas such as the UK, where there is relatively little iodine deficiency, more than 90% of spontaneous hypothyroidism is due to autoimmunity. Anti-thyroglobulin autoantibodies are present in 60% of cases and anti-microsomal antibodies (now identified as anti-thyroid peroxidase antibodies) are present in up to 90%. Antibodies that block the TSH receptor may also be present. Similar antibodies are present in Graves’ disease, but the anti-TSH receptor antibodies are stimulatory, causing the thyrotoxicosis. The eye signs in thyroid disease are shown in the box (see also Chapter 17, Ophthalmology). Retroorbital inflammation and swelling of the extraocular muscles are only seen in Graves’ disease. Note that each of the features listed can occur separately in thyroid eye disease (eg diplopia without exophthalmos) and, surprisingly, disease of the two eyes is usually asymmetrical. The target of the antibody or T-cell reaction causing this inflammation is not known for certain, and eye disease activity can occur in the absence of thyrotoxicosis and even with hypothyroidism. Thyrotoxicosis from any cause • Lid retraction • Lid lag Graves’ disease only • • • • Soft-tissue signs: periorbital oedema, conjunctival injection, chemosis Proptosis/exophthalmos Diplopia/ophthalmoplegia Optic nerve compression causing visual failure 4.5.6 Thyroid function tests TSH is the most sensitive measure of thyroid status in patients with an intact pituitary. T4 and T3 are over 95% protein-bound, predominantly to TBG. The conditions in the box alter TBG levels and hence total, but not free, hormone levels. Conditions that alter thyroid-binding globulin (TBG) Raised TBG Pregnancy Oestrogen Hepatitis Congenital TBG abnormality Low TBG Nephrotic syndrome Congenital TBG abnormality Interpretation of thyroid function tests This is generally straightforward in ambulant out-patients if the causes of different patterns of thyroid function tests (TFTs) are known (Table 4.6). Special care in interpretation should be taken in the following circumstances: • Known or suspected pituitary disease (TSH is misleading and should NOT be used as a test) • Acutely ill patients (eg in intensive care) – TSH often low with low free T3 (fT3) • Patients taking T3 supplements alone. 4.6 ADRENAL DISEASE AND HIRSUTISM 4.6.1 Cushing syndrome Cushing syndrome refers to the sustained over-production of cortisol (hypercortisolism), which causes the following: • • • • • • • • centripetal obesity with moon face ‘buffalo hump’ hirsutism recurrent infections osteoporosis oligomenorrhoea hypokalaemia striae Table 4.6 Thyroid function tests • • • • • acne proximal muscle weakness hyperglycaemia psychiatric disturbances hypertension. If untreated, the mortality rate is high (59% within 5 years), and death is usually due to cardiovascular disease or infection. Fortunately, apart from iatrogenic Cushing syndrome secondary to steroid use, Cushing syndrome is rare. Other endocrine causes of obesity should be excluded: • • • • • hypothyroidism leptin deficiency hypothalamic tumours (hyperphagia) Prader–Willi syndrome GH deficiency. Possible causes of Cushing syndrome are: • Adrenal tumour • Pituitary tumour (Cushing’s disease) • Ectopic production of ACTH – either from cancer (eg small-cell cancer of lung) or from a bronchial adenoma (often very small) • Ectopic production of corticotrophin-releasing hormone (CRH) (very rare). The diagnosis of Cushing’s is made in three phases. Screening tests • Loss of diurnal variation (midnight cortisol similar to morning cortisol) Overnight dexamethasone suppression test (1 mg at midnight then 9am cortisol). Cortisol should • suppress to <50 nmol/L • Raised urinary free cortisol (24-hour collection). Diagnostic tests Low-dose dexamethasone suppression test (0.5 mg four times daily for 48 hours). Cortisol should suppress to <50nmol/l ACTH will be inappropriately normal/raised in pituitary (Cushing’s disease) or ectopic ACTH • secretion, both of which are referred to as ‘ACTH-dependent Cushing syndrome’ ACTH will be suppressed in adrenal disease (Cushing syndrome or ‘non-ACTH-dependent • Cushing syndrome’). • If one or more of these are positive then one can proceed to localisation. Note that depression or alcoholism can cause cortisol overproduction (‘pseudo-Cushing syndrome’). If these conditions are present, further investigation is very difficult. Localisation studies High-dose/low-dose dexamethasone suppression test (2 mg four times daily for 48 hours). • ACTH levels suppress by 50% in 50% of people with pituitary disease, but not with ectopic production. Many have now abandoned this test due to lack of sensitivity MRI of the adrenal or pituitary alone cannot be relied on to localise the cause. First, the tumours of the pituitary causing Cushing’s disease are often too small to see and, second, incidental • tumours of both the pituitary and adrenal are common and may not be functional. Tests used to identify the causes of Cushing syndrome are shown in Table 4.7 Inferior petrosal sinus sampling (IPSS) is an invasive radiological technique in which blood samples are drawn from the sinuses, draining the left and right sides of the adrenal gland, and • also from the periphery. By looking at the ACTH gradients between samples, localisation may be determined. However, due to cross-drainage and difficulties in cannulating the sinuses, results may be difficult to interpret. Treatment of Cushing syndrome The aim of treatment is to normalise cortisol levels. Primary treatment is therefore surgical resection of the tumour with either pituitary or adrenal surgery. Surgery Pituitary Cushing’s disease is primarily treated with transsphenoidal surgery (successful in approximately 60% of cases). ‘Biochemical cure’ is achieved if post-operative cortisol levels are undetectable, as nontumorous pituitary tissue will have been dormant in the presence of the ACTH-producing tumour and may remain dormant for up to 2 years post-operatively. During this time, the patient will require cortisol replacement therapy. Sometimes recovery never occurs and the patient remains permanently ACTH-deficient. If surgical cure has not been achieved, due to incomplete resection of the tumour, then pituitary radiotherapy or medical treatment may be offered. Adrenal Adrenal cortisol-secreting tumours are usually treated with laparoscopic resection, although occasionally this is not possible due to the large size. The whole adrenal is resected and cortisol levels should be undetectable post-operatively, as the contralateral adrenal gland will be dormant due to lack of ACTH stimulation. Recovery of this adrenal gland may take up to 2 years, although, as with the pituitary gland, this may never occur and the patient will remain cortisol-dependent. Failure to cure because of incomplete resection may be treated medically. Table 4.7 Tests used to identify causes of Cushing syndrome Adrenal Pituitary ACTH High-dose dexamethasone suppression Suppressed No change in cortisol Mid-range High a Suppression of cortisol No change CRH stimulation test No change Rise in ACTH and cortisola No change Metyrapone Rise in 11deoxycortisol <220fold Rise in 11deoxycortisol >220folda Rise in 11deoxycortisol <220fold Petrosal sinus sampling Higher than peripheral Equals peripheral level level ACTHb Ectopic Equals peripheral level a’Under pressure’ (ie at high doses), pituitary adenomas behave like a normal pituitary in dynamic endocrine testing, whereas adrenal or ectopic sources do not. A positive response to high-dose suppression (2 mg four times daily for 48 h) is >10% suppression of plasma cortisol or 24-hour urinary free cortisol. bIn a petrosal sinus sampling, a catheter is placed in the draining sinus of the pituitary gland, via a femoral or jugular venous approach. The ACTH level is compared with that in the peripheral blood before and after CRH injection. Occasionally, bilateral adrenalectomy is performed when it is not possible to normalise ACTH secretion (source unknown, or pituitary surgery/radiotherapy has been ineffective). This causes cortisol deficiency but may result in Nelson’s syndrome: loss of suppression (provided by the previously high cortisol levels) may allow a pre-existing pituitary adenoma to grow very rapidly, years later, causing local damage and generalised pigmentation. Radiotherapy Pituitary irradiation may reduce ACTH production and reduce tumour growth. It is insidious in onset but can be effective for up to 15 years. Medical therapy Where surgery is not possible, normalisation of cortisol levels can be sought with metyrapone (although long-term complications include hirsuitism and hypertension) and more recently SOM230, which also inhibits cortisol production. Ketoconazole, previously used with a similar intent, has recently been withdrawn because of concerns of hepatotoxicity. Mitotane can be used in patients with adrenal cortical carcinoma as adjunct chemotherapy. However, medical therapies rarely normalise cortisol levels long term. 4.6.2 Primary hyperaldosteronism Primary hyperaldosteronism comprises hypertension, hypokalaemia (80% of cases), hypomagnesaemia and metabolic alkalosis. Patients can, however, have a serum potassium within the normal range. Primary hyperaldosteronism is now thought to account for 1–3% of all cases of hypertension. • • • • Symptoms (if present) relate to hypokalaemia: weakness, muscle cramps, paraesthesiae, polyuria and polydipsia. Patients rarely develop peripheral oedema (‘sodium escape’ mechanism) Causes: aldosterone-secreting adenoma (Conn’s syndrome is almost never caused by a malignancy), idiopathic bilateral adrenal hyperplasia, unilateral hyperplasia (rare) Investigations (not standardised): the aldosterone:renin ratio (ARR) should be assessed to confirm high aldosterone levels in the presence of low renin. Ideally, the ratio should be assessed after the patient has ceased antihypertensive drugs (β blockers reduce renin levels and therefore increase the ARR, giving a false-positive result. Spironolactone, calcium channel blockers, ACE inhibitors and angiotensin antagonists increase renin levels causing a lowering of ARR and therefore a false-negative result. Alpha blockers (eg doxazosin) have the least effect. Ideally, where possible, these agents should be stopped to allow a washout period of between 4 and 6 weeks. If hyperaldosteronism is confirmed, a CT or MR scan of the abdomen may identify a unilateral adrenal adenoma. However, the tumours are usually <2 cm in diameter and so, if imaging is negative, adrenal vein sampling may be required in order to distinguish unilateral hypoplasia or a tiny adenoma from idiopathic bilateral hyperplasia Treatment: spironolactone and amiloride are often successful treatments when the cause is bilateral hyperplasia. Eplerenone is a selective aldosterone antagonist that can be used in patients who develop gynaecomastia or breast soreness with spironolactone. An adenoma or unilateral adrenal hyperplasia may be surgically removed; hypertension may persist if this was previously long-standing. (See Chapter 1, Cardiology, Section 1.9.3 Systemic hypertension. See also Chapter 15, Nephrology, Section 15.3.4 for differential diagnoses of hypokalaemia.) 4.6.3 Congenital adrenal hyperplasia Two enzyme defects account for 95% of all CAH: • 21-hydroxylase (90%) • 11-hydroxylase (5%). The block caused by these enzyme defects leads to reduced production of cortisol, but increased production of other intermediates in steroid metabolism, including androgenic steroids. 17hydroxylase, 3-β-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage enzyme defects are very rare causes of congenital adrenal hyperplasia (CAH) and have different effects (see the box). Features of congenital adrenal hyperplasia • Autosomal recessive • Both gene deletions and point mutations can occur • Plasma ACTH is high (renin is high if salt-losing) Can cause male precocious puberty (not 17-hydroxylase or side-chain enzyme); can cause • ambiguous genitalia in females (not 17-hydroxylase or side-chain enzyme) • Treat with glucocorticoids mineralocorticoids at night • Can have a minor, late-onset form resembling polycystic ovary syndrome • Surgery may be required to correct ambiguous genitalia/cliteromegaly • Antenatal steroid therapy to the mother has been used It is possible to distinguish between the different enzyme defects in CAH (Table 4.8). Table 4.8 Differentiating features in congenital adrenal hyperplasia 21-hydroxylase 11-hydroxylase 17hydroxylase/sidechain enzyme Frequency 90% cases 5% cases Very rare Presentation in females Virilising, intersex 70% salt- Virilising, hypertension, low Non-virilising (intersex in boys) losinga K+ Biochemistry Raised 17-hydroxylase, progesterone aSalt-losing individuals can have Addisonian crises soon after birth. Raised 11-dehydroxycortisol 4.6.4 Hypoadrenalism In the UK, spontaneous hypoadrenalism is most commonly due to autoimmune destruction of the adrenal glands (Addison’s disease – adrenal autoantibodies present in 70% of cases). Vitiligo is present in 10–20% of cases and can be associated with other autoimmune diseases. Other causes of primary adrenal insufficiency include tuberculosis (TB), HIV or haemorrhage into the adrenal glands. Secondary hypoadrenalism is due to ACTH deficiency, most commonly caused by a pituitary lesion. Hypoadrenalism after withdrawal of longstanding steroid therapy is similar to secondary hypoadrenalism. The following are ‘recognised’ features of hypoadrenalism: Biochemical: raised urea, hypoglycaemia, hyponatraemia, hyperkalaemia, raised TSH, hypercalcaemia • Haematological: eosinophilia, lymphocytosis, normocytic anaemia Clinical features: weight loss, abdominal pain, psychosis, loss of pubic hair in women, • hypotension, auricular cartilage calcification, increased pigmentation. • Hyperkalaemia and increased pigmentation are absent in secondary hypoadrenalism, because there are low levels of circulating ACTH and mineralocorticoids continue to be secreted via the renin– angiotensin–aldosterone system. The gold standard in diagnosing hypoadrenalism is by failure of plasma cortisol to rise above 550 nmol/L at 30 or 60 min after intramuscular or intravenous injection of 250 g synthetic ACTH (short Synacthen 1 test). Treatment is with steroid replacement, and this is most commonly done with oral hydrocortisone. Patients are told to double their steroid doses in times of stress or intercurrent illness. It is imperative that steroid replacement is not stopped, and therefore if patients are unable to take their tablets for any reason (ie vomiting), they are told to seek medical attention. Acute adrenal failure (Addisonian crisis) Acute adrenal failure is one of the few endocrine emergencies. Addisonian crisis presents with hypovolaemia, hyponatraemia, hyperkalaemia (if primary adrenal failure), hypoglycaemia and cardiovascular collapse, which can be fatal. A mildly raised TSH may also be seen even in the absence of thyroid disease. Urgent treatment is necessary, and this includes intravenous fluid and electrolyte replacement as well as, most importantly, steroid replacement. All patients with hypoadrenalism are advised to wear/carry a MedicAlert bracelet with them at all times. 4.6.5 Polycystic ovary syndrome and hirsutism Hirsutism (Table 4.9) is the increased growth of terminal (dark) hairs in androgen-dependent areas. Virilisation is temporal hair recession (male pattern), breast atrophy, voice change, male physique and (most important) cliteromegaly. Hirsutism and acne are invariably also present. A serum testosterone 4.5 nmol/L (normal <1.8 nmol/L), recent onset of hirsutism and signs of virilisation in women should prompt a search for other causes (eg Dehydroepiandrostenedione (DHEA) is a weak androgen produced in the adrenal only. a tumour). Measure the 17-hydroxyprogesterone level after stimulation with ACTH to check for late-onset 21-hydroxylase deficiency (partial enzyme deficiency) Other than androgens, the drugs listed strictly cause hypertrichosis, an increase in vellus hair, • rather than an increase in androgen-sensitive terminal hairs (see Chapter 3, Dermatology). • Polycystic ovary syndrome There is no widely recognised definition, and up to 20% of women have a degree of hirsutism. In practice, the three main presenting complaints in polycystic ovarian syndrome (PCOS) are hirsutism/acne, oligo-/amenorrhoea and subfertility. The following are recognised associations of PCOS: Table 4.9 Causes of hirsutism Ovarian Adrenal Drugs PCOS (<90% of cases) Virilising tumour CAH (may be late onset) Cushing syndrome/adrenal carcinoma Minoxidil Phenytoin Diazoxide Ciclosporin Androgens CAH, congenital adrenal hyperplasia; PCOS, polycystic ovarian syndrome. Clinical features: obesity, acanthosis nigricans, oligomenorrhoea, polycystic ovaries, subfertility, hypertension, premature balding in male relatives, hirsutism Biochemical: insulin resistance and hyperinsulinaemia, raised testosterone, raised LH/FSH • ratio, raised prolactin, low HDL. • Treatment: metformin will lower insulin resistance and it has been shown to promote ovulation, improve conception rates and reduce hirsutism. Weight loss may also be beneficial. Separate specific treatments are available for hirsutism (eg flutamide, cyproterone, finasteride, topical creams) and infertility (ovulation induction). 4.7 PHAEOCHROMOCYTOMA NEOPLASIA SYNDROMES AND MULTIPLE ENDOCRINE Phaeochromocytomas are rare tumours of the adrenal medulla or ganglia of the sympathetic nervous system. They are the ‘tumour of 10%’: • 10% are outside the adrenal glands – paragangliomas (including organ of Zuckerkandl) • 10% are multiple (eg bilateral) • 10% are malignant • 10% are familial. The most sensitive and specific test for the diagnosis of phaeochromocytoma is the measurement of plasma or urinary fractionated metanephrines. This is not available in all centres and measurement of urinary catecholamines is an alternative (measurement of urinary catecholamine metabolites – 3methoxy-4-hydroxymandelic acid or vanillylmandelic acid [VMA] – has now been superseded). As is the case with most endocrine tumours, the histology is not a reliable guide to the malignant potential in phaeochromocytomas. The diagnosis of malignancy is made by the presence of metastases. Familial phaeochromocytomas occur in • Multiple endocrine neoplasia type 2 (see below) • Spontaneously in some families (not associated with a syndrome) Von Hippel–Lindau syndrome (retinal and cerebral haemangioblastomas and renal cystic • carcinomas) • Von Recklinghausen’s disease (neurofibromatosis) – 1–2% • Carney’s triad: gastric leiomyosarcoma, pulmonary chondroma, Leydig’s testicular tumour Paraganglioma syndromes (PGL types 1–4): associated with head and neck paragangliomas and • phaeochromocytomas. Mutations in one of the four succinate dehydrogenase subunits (SDH), especially SDHD (PGL1) and SDHB (PGL 4) Important features of phaeochromocytomas • • • • • • • 70% have persistent rather than episodic hypertension The triad of headache, sweating and palpitations is said to be >90% predictive Extra-adrenal tumours do not make adrenaline (they secrete noradrenaline/dopamine) Hypotension or postural hypotension may occur, particularly if adrenaline is produced They give characteristically a ‘bright’ (white) signal on T2-weighted MRI MIBG (m-iodobenzylguanidine) scanning may help localisation Phaeochromocytomas may produce chromogranin A Preoperative preparation is with α-adrenergic blockade (eg phenoxybenzamine) before β • blockade Causes of episodic sweating and/or flushing • • • • Oestrogen/testosterone deficiency (eg menopause, castration) Carcinoid syndrome (flushing, diarrhoea, wheeze) Phaeochromocytoma (sweat but do not flush) Hypoglycaemia (in diabetes) • Thyrotoxicosis (not usually episodic) • Systemic mastocytosis (histamine release) • Allergy. Multiple endocrine neoplasia (MEN) syndromes are syndromes with multiple benign or malignant endocrine neoplasms (Table 4.10). They should not be confused with polyglandular autoimmune syndromes which relate to autoimmune endocrine diseases. Table 4.10 Classification of multiple endocrine neoplasia (MEN) Genetics Tumours MEN-1 MEN-2A MEN-2B The menin gene Chromosome 11 The ret gene Chromosome 10 Parathyroid Pituitary Pancreas (carcinoid) (Adrenal adenomas) Parathyroid Phaeochromocytoma Medullary thyroid cancer The ret gene Chromosome 10 Parathyroid Phaeochromocytoma Medullary thyroid cancer Marfanoid Mucosal neuromas MEN-1 was formerly known as Werner’s syndrome. MEN-2A was known as Sipple’s syndrome. All MEN syndromes are autosomal dominant. Genetic (DNA-based) screening is available for • both MEN-1 and MEN-2. The MEN-2 mutation in ret activates the protein. Inactivating mutations of ret are seen in Hirschsprung’s disease All MEN syndromes can be associated with hypercalcaemia. This is usually due to hyperplasia • of all four parathyroids, not a single parathyroid adenoma as with sporadic hyperparathyroidism. Hypercalcaemia is often the first manifestation in MEN-1 Gastrinomas and insulinomas are the most common pancreatic tumours in MEN-1. Of the • pituitary tumours, prolactinomas are the most common, followed by acromegaly and Cushing’s disease. Medullary thyroid cancer (MTC) is always malignant, secretes calcitonin and is preceded by C-cell hyperplasia. Prophylactic thyroidectomy in patients with genetically confirmed MEN-2 should be performed to prevent this most serious manifestation. The exact site of the ret gene determines the age at which thyroidectomy should be performed, in many cases under the age of 2 years. 4.8 PUBERTY/GROWTH/INTERSEX 4.8.1 Normal puberty In 95% of children, puberty begins between the ages of 8 and 13 years in females and 9 and 14 years in males. The mean age of menarche is 12.8 years. The events of puberty occur in a particular order, although the later stages overlap with the earlier ones. Order of events in normal puberty (earliest events listed first) • Male • Scrotal thickening (age 9–14) • Testicular enlargement (>2 mL) • Pubic hair • Phallus growth • Growth spurt (age 10–16) + increasing bone age • Female • Breast development (age 8–13) • Growth spurt • Pubic hair • Menstruation (age 10–16) + increasing bone age 4.8.2 Precocious puberty True precocious puberty is rare. It is diagnosed if multiple signs of puberty develop before age 8 in females and age 9 in males, accompanied by increased growth rate, accelerated bone age and raised sex steroid levels. Isolated premature breast development (thelarche) or the appearance of pubic hair alone (from adrenal androgens – adrenarche) are both benign conditions if no other stages of puberty are entered. Causes of precocious puberty • True ‘central’ gonadotrophin-dependent precocious puberty • Idiopathic • Other CNS disease (eg hydrocephalus, encephalitis, trauma) • CNS hamartoma (eg pineal) • Other causes (gonadotrophin-independent) • Adrenal, ovarian tumour • CAH (males) • Testotoxicosis (males) • Exogenous oestrogen (females) • McCune–Albright syndrome • Follicular cysts (females) • Profound hypothyroidism McCune–Albright syndrome is more common in girls (see Section 4.1.2 on activating G-protein mutations). 4.8.3 Delayed puberty/short stature Short stature in children is often due to delayed puberty and hence the two problems are usually grouped together. Three per cent of children are ‘statistically delayed’, ie for girls no breast development by age 13 or menses by age 15, and for boys no testicular enlargement by age 14. The majority will have ‘constitutional delay’ and will later enter puberty spontaneously. However, there is no endocrine test that can reliably distinguish constitutional delay from other organic causes of delayed puberty. In investigation, systemic diseases or syndromes that can cause delayed puberty should be excluded before considering pituitary testing. A karyotype (for Turner’s syndrome) should always be requested in girls (see following text). Causes of delayed puberty/short stature • General causes • Overt systemic disease • Social deprivation • Anorexia, excess exercise • Chemotherapy/gonadal irradiation • Cranial irradiation • Syndromes causing delayed puberty/short stature • Turner’s syndrome (XO) • Noonan’s syndrome (‘male Turner’s syndrome’) • Prader-Willi syndrome • Occult systemic disease • Renal failure/renal tubular acidosis • Crohn’s/coeliac disease • Hypothyroidism • Asthma • Anterior pituitary disease • Hyperprolactinaemia • Isolated GH deficiency • Syndromes causing delayed puberty but normal stature • Androgen insensitivity (testicular feminisation – XY female) • Polycystic ovary syndrome (delayed menarche only) • Kallman’s syndrome (XY), anosmia • Klinefelter’s syndrome (XXY) – males In Turner’s syndrome, Noonan’s syndrome, androgen insensitivity and Klinefelter’s syndrome, raised LH and FSH are present. Kallman’s syndrome is due to failure of GnRH-secreting neurons migrating to the hypothalamus. LH and FSH levels, as well as sex steroids, are low and patients typically have associated anosmia. Mutations in at least five genes can cause the syndrome, the best recognised being the classic X-linked locus (KAL-1 also known as anosmin-1 – the syndrome associated with anosmia) and the autosomal loci fibroblast growth factor receptor 1 (FGFR1, a syndrome associated with orofacial clefting and hypodontia). However, gene mutations account for only around 40% of cases of idiopathic hypogonadotrophic hypogonadism. There is no biochemical test that can currently distinguish Kallman’s syndrome from constitutional delay of puberty, and therefore a clinical diagnosis is made when delayed puberty is associated with anosmia. Turner’s syndrome (XO) (see Chapter 7, Genetics) occurs in 1 in 2500 live births. The typical features (abnormal nails, neonatal lymphoedema, web neck, widely spaced nipples, wide carrying angle) may be absent. A karyotype should always be requested in girls with short stature/delayed puberty because the final height can be increased by early treatment with high doses of growth hormone. Other important complications which may occur in Turner’s syndrome include aortic root dilatation (often the cause of death) or coarctation, renal abnormalities, abnormal liver function tests and deafness. Women with Turner’s syndrome are generally infertile, but in some cases will have relatively minor X deletions and/or chimaerism with cells of a normal karyotype, so both menstruation and pregnancy can occur. Klinefelter’s syndrome (XXY) (see Chapter 7, Genetics) occurs in 1 in 1000 live births (by meiotic non-disjunction), but is usually undiagnosed until adulthood. Testosterone production is around 50% of normal, but is sufficient to allow secondary sexual characteristics and normal height to develop. Patients usually come to attention because of small testes, gynaecomastia or infertility. 4.8.4 Intersex (See also Chapter 7, Genetics.) Ambiguous genitalia at birth require urgent diagnosis with steroid profile and karyotype to assign the appropriate sex of rearing and identify the risk of a salt-losing crisis (CAH). Causes can be grouped as shown in the box. Causes of intersex • Virilised female (XX) • CAH (21-OH or 11-OH) • Maternal androgen ingestion • Non-masculinised male (XY) • Unusual CAH (17-OH/side-chain/3-β-OH) • Androgen resistance: • Receptor defect (‘testicular feminisation’) • 5α-reductase deficiency Mothers who have a virilised daughter with CAH can be treated antenatally with steroids in subsequent pregnancies in order to suppress androgen production by the fetus. Steroids are continued until the sex of the baby can be established by chorionic villous sampling. 4.9 DIABETES MELLITUS Diabetes may be defined as chronic hyperglycaemia at levels sufficient to cause microvascular complications: 10% of cases are due to type 1 diabetes where there is autoimmune destruction of the pancreatic islets of Langerhans Around 85% are due to type 2 diabetes characterised by insulin resistance and relative • deficiency of insulin secretion • The remaining 5% of cases are due to a collection of secondary causes • 4.9.1 Risk factors and clinical features of types 1 and 2 diabetes mellitus Table 4.11 summarises the differences between type 1 and type 2 diabetes mellitus. Note that type 2 diabetes is more common in non-Caucasian races and is actually more strongly inherited than type 1 diabetes, despite being ‘adult-onset’. Table 4.11 Comparison between type 1 and type 2 diabetes mellitus Genetics Type 1 Type 2 Both parents affected: up to 30% risk for child Identical twins: 64% concordance by 60 years Both parents affected: 75% risk for child Identical twins: up to 90% concordance Caucasians Increased risk conferred by over 15 gene loci identified so far, the more of these present, the greater the risk Autoantibodies Asian, Black, Hispanic, Native Americans Over 20 genes have been identified that increase susceptibility In new type 1 diabetics: 60– 75% have insulin antibodies 70–80% have GAD (glutamic acid decarboxylase) antibodies No antibody association 65–75% have IA-2 (islet antigen-2) antibodies 70–80% have ZnT8 (zinc transporter-8) antibodies Incidence Approximately 1/10 000 per year and rising Approximately 1/200 per year Prevalence Approximately 1/1000 Approximately 5/100 Age <40 Clinical features Weight loss Ketosis prone Insulin deficient Autoimmune aetiology (other autoimmune disorders may be present) Age usually >20 but increasing numbers of paediatric patients Insidious onset Overweight Usually ketone negative Insulin resistant Acanthosis nigricans Associated with metabolic syndrome (with obesity, hypertension, dyslipidaemia) Maturity onset diabetes of the young (MODY) is a term used to describe a group of disorders describing autosomal dominantly inherited monogenic diabetes. It causes 1–2% of diabetes and there is usually a family history. Age of onset of diabetes is usually less than 25 years and the condition is caused by beta cell dysfunction. Treatment depends on the underlying gene defect (Table 4.12). 4.9.2 Diagnostic criteria for diabetes This remains an area of ongoing debate. There have been recent changes to the diagnostic criteria for diabetes with the official addition of the use of HbA1c for diagnosis rather than to solely look at glycaemic control. The current practical use of the OGTT (oral glucose tolerance test) is for those patients with a fasting glucose level between 6.0 and 7.0 mmol/L, or in the diagnosis of gestational diabetes. Diagnoses of diabetes and pre-diabetes* • • • • • With symptoms: fasting glucose >7.0 mmol/L or random glucose over 11.1 mmol/L or glucose over 11.1 mmol/L 2 hours into an OGTT HbA1c ≥48 mmol/mol or 6.5% Without symptoms: fasting glucose >7.0 mmol/L or random glucose 11.1 mmol/L on 2 occasions Impaired glucose tolerance is defined by a 2 hour OGTT value of 7.8–11.1 mmol/L Impaired fasting glucose is a value > 5.6 but <7.0 mmol/L. *Values are based on venous rather than capillary blood values. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two conditions of ‘prediabetes’. IGT confers increased cardiovascular risk. Twenty percent of patients with IGT will progress to type 2 diabetes within 5 years. A number of interventions have been identified that can reduce the risk of this occurring or slow the progression. A programme of diet and exercise, weight loss (any cause including bariatric surgery), and drugs including metformin, acarbose, thiazolindenediones and orlistat have all been shown to be effective. Table 4.12 Classification of MODY (maturity-onset diabetes of young people) disorders Gene Percentage of MODY cases Glucokinase 20 HNF-1α 60 HNF-4α 1 HNF 1β 1 IPF-1 Unknown 1 <1 15 SUR1, Kir6.2 <1 Classification of diabetes • Type 1 diabetes • Type 2 diabetes • Genetic disorders • MODY • Mitochondrial disorders eg MELAS, MIDD • Exocrine pancreas disease eg • Pancreatitis • Pancreatectomy • Haemochromatosis • Cystic fibrosis • Neoplasm • Drugs eg corticosteroids, antipsychotics • Endocrine disorders eg • Cushings • Acromegaly • Thyrotoxicosis Classification MODY 2 – mild, complications are rare MODY 3 – progressive beta cell failure but very sensitive to sulphonylureas 1 MODY 1 – neonatal hyperinsulinism MODY 5 – associated renal anomalies or cysts MODY 4 – very rare MODY 6–11 MODY X Hyperinsulinism in infancy and βcell failure in adulthood • Phaeochromocytoma • Other genetic syndromes eg • Down’s syndrome • Klinefelter’s syndrome • Turner’s syndrome Wolfram syndrome (also known as DIDMOAD – diabetes insipidus, diabetes Mellitus, optic • atrophy and deafness) • Gestational diabetes mellitus 4.9.3 Treatment of type 1 diabetes Insulin replacement is essential in type 1 diabetes. There is ample evidence to show that improved glycaemic control reduces the risk of complications. Subcutaneous insulin administration can vary from two to five injections per day. Multiple dose regimes with a combination of basal insulin (intermediate or usually long acting) and varying doses of rapid-acting insulin meals according to capillary glucose levels, carbohydrate intake and exercise, allow greater flexibility and improve control. In the UK, NICE has licensed continuous subcutaneous insulin infusions (CSII, insulin pumps) for type 1 diabetics in whom multiple dose regimes of insulin have not improved control sufficiently (HbA1c over 8.5%, 69mmol/mol) or led to disabling hypoglycaemic episodes. Additional treatments include islet cell transplantation and whole pancreas transplantation, which may be indicated in patients with recurrent severe hypoglycaemia despite best medical treatment. In addition, cardiovascular risk factor management is also indicated in all patients. Types of insulin are shown in Table 4.13. Table 4.13 Types of insulin Rapid Short Intermediate Long Mixed 4.9.4 Examples Peak (hours) Duration (hours) Aspart, Lispro Regular NPH Detemir Glargine Insuman Comb 25 Humulin M3 1 3–4 2–4 6–8 4–8 12–16 – 18–24 – 20–24 Varies depending on type – combined intermediate and rapid acting insulin Treatment of type 2 diabetes There are a number of drug categories available to treat patients with type 2 diabetes (Table 4.14), and drug choice needs to be based on a number of factors including glycaemic control, patient preference, side effects and associated comorbidities. A gradual decline in insulin reserves leads to an increasing requirement for medication and around 30% of type 2 diabetics ultimately need insulin therapy to achieve glycaemic targets. Weight loss (whether by diet and exercise, medication or bariatric surgery) is an important adjunct to medication to improve glycaemic control, and in some cases can cause the remission of diabetes. In addition, cardiovascular risk reduction with control of hypertension, lipids and the use of aspirin are important for management. Table 4.14 Drugs used in the glucose control of type 2 diabetes Drug Action/comments Sulphonylureas Increase insulin secretion; risk of hypoglycaemia, weight gain Biguanides (eg metformin) Reduced insulin resistance (lower hepatic glucose production). GI side effects. Rare risk of lactic acidosis (usually in the context of concurrent illness and reduced GFR) α-Glucosidase inhibitors (eg Slows carbohydrate absorption. Unacceptable flatus production for acarbose) most patients Thiazolindenediones (eg pioglitazone) Activate intracellular PPAR-γ thereby reducing insulin resistance. Can cause fluid retention, osteoporosis and link with bladder cancer Insulin Used frequently in combination with other drugs; causes weight gain Glucagon-like peptide agonists (eg exenatide) Increase secretion of endogenous insulin, suppress glucagon, reduce appetite and promote weight loss. Injected Dipeptidyl peptidase IV inhibitors (eg sitagliptin) Increase secretion of endogenous insulin. No weight gain SGLT-2 inhibitors (eg dapagliflozin) Allow glycosuria by blocking glucose reabsorption in the kidneys. Some weight loss. Increased risk of urinary tract infections 4.9.5 Glycated HbA1c Red cell haemoglobin is non-enzymatically glycated at a low rate according to the prevailing level of glucose. The percentage of glycated haemoglobin provides an accurate estimate of mean glucose levels over the preceding 2–3 months and correlates with the risk of microvascular complications. Modern assays for HbA1c are rarely misleading but a few considerations should be made if home glucose monitoring results don’t correlate well: Abnormally low HbA1c • Haemolysis • Increased red cell turnover • Blood loss • HbS or HbC Abnormally high HbA1c • Persistent HbF • Thalassaemia • Uraemia (carbamylated haemoglobin) One thing this does highlight is the potential pitfall of using HbA1c in the diagnosis of diabetes – care must be taken if there is a high red cell turnover or if symptoms are of a rapid onset. 4.9.6 Microvascular and macrovascular complications of diabetes Long-term diabetic complications are due to vascular damage. Damage to the microvasculature and its consequences correlate well with levels of glycaemic control and can be delayed or prevented by maintaining near-normal glucose levels. Microvascular complications usually take a minimum of 5 years to develop, even with poor glycaemic control. In paediatric cases, the changes in hormones during puberty lead to acceleration of risk as compared to pre-puberty. Complications may be apparent at diagnosis in type 2 diabetes due to delayed diagnosis. Neuropathy (70–90%) and retinopathy (90%) occur in virtually all patients with suboptimal control and longer duration of diabetes. Thirty to forty per cent of patients will develop diabetic nephropathy, usually within 20 years of onset of diabetes. The incidence of microvascular complications was reduced in type 1 diabetics by around 50% in the Diabetes Control and Complications Trial (DCCT) by tight glycaemic control. In contrast, macrovascular disease, which is responsible for most of the increased mortality in diabetes, does not appear to be as closely related to the level of glycaemic control. The increased risk of macrovascular disease is partly explained by a combination of hypertension, lower HDL and higher triglyceride levels. Treatment of hypertension reduces not only cardiovascular risk but also the risk of neuropathy and retinopathy (especially the use of ACE inhibitors). Note that chest pain due to ischaemic heart disease is often absent or atypical in diabetes and easily missed Proteinuria is a strong risk factor for ischaemic heart disease in diabetes, presumably as a • marker of endothelial dysfunction. Individuals with microalbuminuria or proteinuria should have more aggressive blood pressure control. Peripheral neuropathy predisposes to foot ulceration (occurs in 10% of patients) and, particularly in combination with peripheral vascular disease, increases the risk of amputation • (0.5–1%). Some patients with neuropathy develop Charcot’s osteoarthropathy with collapse of the bony architecture of the foot and development of deformity. • Micro- and macrovascular complications of diabetes • Microvascular • Retinopathy (90%)* • Neuropathy (70–90%)* • Nephropathy (30–40%)* • HbA1c dependent • Macrovascular • Ischaemic heart disease (accounts for up to 70% of deaths in diabetes) • Peripheral Vascular disease • Cerebrovascular disease • Less HbAC1c-dependent *Approximate percentages of diabetics who will have this complication to some degree during their lifetime (data from retrospective studies). 4.9.7 Autonomic neuropathy Autonomic complications of diabetes may occur in long-standing diabetes, especially in the context of poor control. Complications can be very difficult to treat and there is high morbidity, reduced quality of life and increased mortality. Manifestations of diabetic autonomic neuropathy • • • • • • • Postural hypotension Gastroparesis Gustatory sweating Generalised sweating Cardiac arrhythmia (‘dead in bed’) Diarrhoea, constipation Reduced appreciation of cardiac pain 4.10 HYPOGLYCAEMIA 4.10.1 Hypoglycaemia in diabetes mellitus Autonomic symptoms of hypoglycaemia (sweating, tremor) appear when the blood glucose is <3.5 mmol/L, but can also occur at higher levels when diabetics have poorer glycaemic control, or when there is a rapid drop in glucose levels. Neurogycopaenic symptoms (impaired cerebral function, coma, seizures) occur when glucose levels drop <2.5 mmol/L. In patients on insulin, failure of the normal counter-regulatory responses (sympathetic nervous system activation, adrenaline and glucagon release) may develop in long-standing diabetes, particularly in the context of frequent hypoglycaemic episodes. This results in hypoglycaemic unawareness. With no warning of impending neurological impairment, the patient cannot take appropriate action. More frequent hypoglycaemic episodes result, exacerbating the problem – ‘hypos beget hypos’. Hypoglycaemic awareness can be restored by relaxing control to allow a prolonged hypoglycaemia-free period. 4.10.2 Hypoglycaemia unrelated to diabetes True hypoglycaemia unrelated to diabetes is relatively rare. Whipple’s triad consists of symptoms consistent with hypoglycaemia, measured hypoglycaemia and resolution of symptoms with correction of the low glucose. A supervised 72-hour fast can be used to precipitate and document an episode, particularly to diagnose an insulinoma (where there will be inappropriately elevated insulin and Cpeptide levels in conjunction with a low glucose level). Causes of hypoglycaemia • Fasting • Insulinoma • Tumour (IGF-2 mediated) • Hypoadrenalism • Alcohol • Severe liver failure • Factitious (insulin or sulphonylurea) • Drugs • Anti-insulin antibodies (delayed postprandial release of insulin) • Post prandial • Post-gastrectomy/bariatric surgery • Reactive • Idiopathic (rare) Chapter 5 Epidemiology Contents 5.1 Introduction 5.1.1 Variables 5.1.2 End-points 5.1.3 Associations 5.1.4 Causation 5.2 Randomised controlled trials 5.2.1 Methods and benefits of randomisation 5.2.2 Trial monitoring 5.2.3 Classifications of randomised trials 5.3 Observational studies 5.3.1 Cohort studies 5.3.2 Case-control studies 5.3.3 Cross-sectional studies 5.3.4 Case reports 5.3.5 Ecological studies 5.4 Interpreting results 5.4.1 Randomised studies 5.4.2 Observational studies 5.5 Systematic review and meta-analysis Epidemiology 5.1 INTRODUCTION Epidemiology is the study of patterns, associations and effects of diseases that affect a specific population. In modern research this definition is often expanded to consider endemic conditions, ie diseases pre-existing within defined populations, and the effects of health states not classically considered to be a disease, eg body mass index. Epidemiological studies can therefore do the following: • Suggest which variables may cause a disease • Describe associations between variables and end-points • Identify possible interventions and their expected clinical effect. 5.1.1 Variables A variable is a characteristic that is not entirely fixed. Differences in a variable can exist between patients, eg male or female, or within patients, eg change in blood pressure over time. When designing a study, it is vital to consider how variables interact. Typically, a study will aim to consider the relationship between an exposure variable and an outcome variable in a specific population, eg does treatment with a statin (exposure variable) alter risk for death (outcome variable) in patients with chronic kidney disease (population)? However, in non-randomised studies, other variables can directly and indirectly impact on exposure and outcome variables. These relationships must be accounted for to provide accurate results. A drawing of the interactions between variables (termed a ‘directed acyclic graph’) is helpful in this situation (Figure 5.1). Confounding A variable that is directly related to both the exposure variable and the outcome variable, but does not link the two, is referred to as a confounder or confounding variable (Figure 5.1a). An example often used to illustrate this is the significant association between ice-cream sales and open water drowning. Here, hot weather is a confounding variable. When it is warm more people buy ice-cream, but also people will be more inclined to swim, thus increasing drowning risk. The relationship between ice-cream sales and drowning is therefore spurious. This highlights the importance of clinical plausibility when interpreting results. Intermediate variables Intermediate variables lie on a direct causal pathway between exposure and outcome variables (Figure 5.1b). An example here is obesity, blood pressure and coronary artery disease. It is known that obesity can increase blood pressure and that increased blood pressure can lead to coronary artery disease. Therefore, when considering if obesity is associated with coronary artery disease, blood pressure is an intermediate variable. Figure 5.1 Two directed acyclic graphs showing possible relationships between variables in an epidemiological study. Effect-modifying variables Where an association exists between exposure and outcome, the strength of association may differ between levels of a given variable, eg increased cholesterol levels are associated with the development of coronary artery disease. However, the relative risk associated with higher cholesterol levels is greatest in younger patients. Age is therefore termed an ‘effect modifier’. This can alternatively be described as a statistical interaction between age and outcome, or as heterogeneity between strata of patient ages. Where effect modifiers exist, it can be helpful to present overall results and results for subgroups, eg all patients, young patients and older patients. 5.1.2 End-points Outcome variables can also be referred to as study end-points. These can be measured in different ways: Number of events: the absolute number of participants in the event who did or did not reach the • outcome under investigation. Typically proportions of patients are described as a percentage. This is termed the ‘incidence proportion’, or ‘average risk’ Rate of events: this describes the number of end-points that occur over a specific time period and is often presented as number of events per 100 patient-years. This is the incidence rate and is calculated by: • Event rate per 100 patient-years = Prevalence: this is the proportion of patients in a given population with a disease at any given • time point. As prevalence is affected by duration of disease, rate of new cases, rate of cure and rate of death, it has greater use in public health studies than in estimating the effect of an exposure variable Survival time: the length of time each patient is in the study before reaching the end-point or • leaving the study. Study end-points should be clearly defined before the study begins. However, some end-points are difficult to study, because they are rare. In these cases other outcome variables thought to be correlated with the end-point of interest are often substituted, eg doubling of creatinine used instead of starting dialysis. This is referred to as a surrogate end-point. It is important to remember that these cannot be directly substituted for the primary endpoint when considering the results. 5.1.3 Associations If, after accounting for confounding, the outcome variable occurs with greater frequency in one exposure group than the other, then the exposure is said to be associated with the outcome. When reading results, it is important to remember that evidence of association is not necessarily evidence of causation, and that the clinical significance (ie real-world utility) of the association must be considered alongside the statistical significance. Associations should therefore be thought of in terms of absolute risk and relative risk. Absolute risk Absolute risk describes what occurs within each exposure group without consideration of confounding effects. This is often presented as the incidence proportion and incidence rate within each exposure group. Absolute risk can be useful when assessing clinical significance and estimating disease burdens at a population level. Relative risk The simplest measures of relative risk are the ratio of incidence rate between exposure groups (the incidence rate ratio), and the ratio of incidence proportion between groups (the risk ratio). These measures begin to provide an estimate of treatment effect, but, as they are based on measures of absolute risk, they do not account for confounding caused by differences between groups. These differences can be accounted for using regression equations that adjust for confounding effects – this is referred to as a multivariate analysis. Odds ratio: this statistic represents the probability of an outcome event in one exposure group relative to the other over a specific time frame. An odds ratio (OR) >1 suggests an increased • risk, and an OR <1 a reduced risk. These can be interpreted as percentages, ie an OR of 1.2 represents a 20% increase in risk, and an OR of 0.7 represents a 30% reduction in risk Hazard ratio: these values are interpreted in the same manner as an OR but can be more useful because information on survival time for each patient is considered. This allows patients with • greatly different times in a study (eg 1 year and 10 years) to be accurately compared with each other in the same analysis Time-varying risk: as variables can change over a study period, eg blood pressure, using a single measurement taken at the start of the study, can lead to inaccurate results. Several approaches can be used to account for these changes, with the simplest being to use an average of • all values. As a hazard ratio incorporates information on survival time; this methodology can be used to calculate risk for each patient between each measurement. Use of time-varying variables allows a greater amount of data to be analysed and therefore provides a more accurate estimate of risk. Examples of absolute and relative risk If in a study of a drug, the relative risk associated with treatment was 0.5 but the population event rate (absolute risk) was only 1 event per 1000 patient-years, then the clinical benefit that a • patient would receive from treatment would be smaller than suggested by looking at the relative risk in isolation If in a western European population the annual incidence rate of coronary heart disease was 100 per 10 000 people in obese patients and 50 per 10 000 people in non-obese patients, whereas in an eastern Asian population it was 10 and 5 per 10 000 people in these two groups, then although the relative risk would still be 2 in both populations, the annual absolute risk would be 50 per 10 • 000 people in the European population, but only 5 per 10 000 people in the Asian population. Thus, although obesity would be as strong a cause of coronary heart disease in the two populations (as indicated by the relative risks), the importance of the association with population health would be much greater in the European population (as indicated by the absolute risks). This is also an example of ethnicity acting as an effect modifier. 5.1.4 Causation The existence of a statistically significant association between an exposure and an outcome variable cannot be taken to mean that a causal relationship exists. To suggest a causal link, the Bradford–Hill criteria should be satisfied: • Temporality: the outcome must follow the exposure • Strength: larger associations are more likely to have a causal relationship • Consistency: associations should be replicated in separate studies Biological gradient: a higher level of exposure is associated with a higher incidence of the • outcome Plausibility: the link between cause and effect should be plausible given what is already known. • The inverse of this statement can also be considered; the effect is probably causal if no other exposure variable is plausibly linked to the outcome Coherence and experimental evidence: the observed association can be placed in a context of • other laboratory and epidemiological studies (this links to consistency and plausibility) Analogy: if a similar association can be demonstrated in another setting it is more likely to be • causal Specificity: the more specific the population, exposure and outcome being considered, the more • likely any association is to be causal. An example is given in Table 5.1. Even when all the Bradford–Hill criteria are addressed, other possibilities should be considered. Chance findings can occur, no matter how statistically significant the results are. More likely are problems related to study design (leading to confounding or selection bias), measurement error or incorrect statistical analysis. 5.2 RANDOMISED CONTROLLED TRIALS Randomised trials randomly allocate patients between exposure variables with the aim of reducing confounding and bias in exposure. These studies are considered ethical where genuine uncertainty exists as to which treatment is the most appropriate. Different methods of randomisation exist. As such they are ideal tools for investigating the effect of a treatment, eg a new drug, but cannot be used to investigate exposures where direct allocation to an exposure group cannot be made, eg diabetes. Randomised trials can be open, where the participants and investigators are aware of exposure assignment, single-blinded where either the participants or the investigators are unaware of exposure assignment, or double-blinded, where both the participants and investigators are unaware of treatment assignment. The benefit of blind studies is that it removes any incentive for patients and investigators to introduce bias to data based on preconceived ideas. Well-designed, run and analysed randomised trials provide the strongest standard of evidence. All randomised trials are required to be registered in the public domain (eg www.clinicaltrials.gov). Such registries provide details of the study design and population of interest, outcome measures, number of participants and intended follow-up period. 5.2.1 Methods and benefits of randomisation Study powering Before starting a randomised trial a power calculation is required. The power of the study is the probability of correctly rejecting the null hypothesis (avoiding a type II error). By defining the power required, the difference expected between exposure groups, and the level of statistical significance required between exposure groups (protection from a type I error), it is possible to estimate the minimum number of participants needed in the study. Increasing the power of the study and the final level of statistical significance required will make the final result more likely to be genuine, but can greatly increase the number of patients needed, especially if the expected effect size (the difference in the outcome variable between exposure groups) is small. Table 5.2 shows the number of patients needed. Table 5.1 Bradford–Hill criteria applied to smoking and lung cancer Bradford–Hill criteria Study results Temporality In almost all cases, smoking preceded development of lung cancer Over a 10-fold increased risk for lung cancer associated with smoking Strength of association Consistency Biological gradient Plausibility Coherence and experimental evidence Analogy Specificity Findings replicated in many different studies and patient groups Greatest risk for lung cancer seen in the heaviest smokers Laboratory data had shown that smoking could cause tissue damage Exposure of animals to cigarette tar had led to development of cancer A causal link between lung cancer and smoking was shown in rats In prospective studies, smoking was the best predictor of developing lung cancer Randomisation techniques Properly conducted randomisation avoids any form of systematic allocation of patients to the exposure group. Assigning patients to an exposure group based on factors such as day of visit, hospital record number or date of birth is not truly random. The simplest form of truly random allocation can be compared with a flip of a coin. Although simple to implement, this approach often results in unequal groups and/or an imbalance in variables between groups. Therefore forms of restricted randomisation are commonly used, including: Block randomisation: recruited patients are allocated to randomisation blocks of a certain • number, eg 10. Within each block, half of the patients are randomised to one exposure and half to another Random allocation: here the entire study population is treated as a single block. A commonly • used example is, for a study of 100 patients, 50 white and 50 black balls placed in a bag. As each patient is recruited, a ball is drawn to define their exposure allocation. Restricted randomisation prevents imbalance in group sizes but cannot protect against uneven distribution of variables between groups. Although in sufficiently large studies this rarely occurs, some small trials use stratified restricted randomisation. Here subsets of patient are identified based on certain characteristics, eg diabetes. These subsets then undergo restricted randomisation separately from the other recruited patients. This aims to create numerically equal groups with evenly distributed variables. 5.2.2 Trial monitoring In addition to outcome data, a range of information, primarily about patient safety, is collected during randomised trials. Treatment compliance: adherence to study medications is regularly assessed, normally by means of a pill count. This is an important measure because poor compliance with medications can alter • study results, usually reducing the estimated treatment effect. High levels of non-compliance should be considered when considering the clinical utility of results Adverse events: all unexpected events that occur during a randomised trial are recorded and a • possible relationship to the study drug considered. This information is important when considering the number needed to treat and number needed to harm. Table 5.2 Number of patients required in each exposure group as required power and statistical significance vary Effect size 10 5 2 Statistical significance set at 0.05 Power 0.80 Power 0.90 Power 0.95 42 55 68 162 217 268 1010 1350 1670 128 162 242 795 1010 1503 Power set at 0.80 Significance 0.1 Significance 0.05 Significance 0.01 33 42 62 A data monitoring committee regularly reviews all available study information. In addition to ensuring that sufficient patients are recruited to the trial, they may terminate the study ahead of schedule for several reasons: Safety concerns: protection of patient safety is the most important consideration. The number and • severity of adverse events is compared between treatment groups. If an imbalance exists, the trial may be stopped Overwhelming benefit: if an early analysis suggests that a new treatment is unequivocally • superior, then it would no longer be ethical to continue the trial Futility: if there is absolutely no benefit of a new treatment seen at a stage when it would have • been expected to be observable, a trial may be stopped in the interests of financial prudence. 5.2.3 Classifications of randomised trials Randomised trials can be classified by their design. The most common form of randomised trial is a parallel group study, where patients are allocated to a single exposure group for the duration of the study. Other study designs include: • Crossover: participants switch exposures at a defined point in the study Factorial: this design is used when more than two exposures can be defined. Patients are • randomised to a combination of possible exposures Cluster: participants are not randomised individually, but instead are randomised by preexisting • groups, eg dialysis unit. Another means of classifying randomised trials is by their outcome measure. For a trial to be ethical, new treatments must be compared with the current, accepted, best treatment. A study that aims to prove the new treatment results in better patient outcomes is termed a ‘superiority trial’. Other designs include non-inferiority and equivalence studies, which aim to demonstrate that a new treatment is no worse than the current standard. These trials are typically performed where a new treatment is cheaper or is thought to have fewer side-effects. 5.3 OBSERVATIONAL STUDIES 5.3.1 Cohort studies Cohort studies are longitudinal and typically observe a specific patient subgroup, eg those with chronic kidney disease. Although many studies are performed over a relatively short time period, some cohort studies, eg the Framingham heart study, have a period of observation in excess of 50 years. As with randomised controlled trials, patient groups are defined by exposures; however, these are not randomly allocated and can be defined in a prospective or retrospective manner. Cohort studies are most commonly used to identify risk factors for the development of disease: Prospective: here patient groups are defined before the period of observation starts, reducing the • risk of introducing selection bias. Follow-up occurs at regular intervals and multiple endpoints can be considered Retrospective: here, data about exposure are collated after the event of interest has occurred. Although this can allow research questions to be answered in a much shorter time, there is a risk of recall bias affecting results. This is due to difficulties that patients can have in remembering • details from a number of years previously. An alternative form of this is response bias, where an apparent difference between groups may be due to only one group being more prepared to discuss a specific health issue. Cohort studies, especially those performed over a period of years, can be heavily influenced by loss of patients to follow-up, whether this is due to choosing to leave the study or death. This can result in only the healthiest patients remaining in the study, introducing bias into the results. Recently, joint models have been developed and are partly able to address this issue. Here, a change in a measured characteristic over time, eg renal function, is analysed in relation to patient survival. 5.3.2 Case-control studies In a case-control study two patient groups, one with a specific outcome/exposure and one without, are identified and compared. Case-control studies are most commonly used to identify variables associated with a disease where little information already exists. To consider the role of smoking in causing lung cancer, the case group would be formed from people with lung cancer and the control group from people without lung cancer. As with retrospective cohort studies, recall bias is a recognised problem. Equally important is the selection of the control group. To allow an accurate comparison to be made, these patients should be drawn from the same population as the cases, have a similar range of other disease risk factors, and have been selected independently of the outcome/exposure in question. Where this is not the case, selection bias will influence results. Due to these potential problems, case-control studies are placed below cohort studies on the hierarchy of evidence (Figure 5.2). 5.3.3 Cross-sectional studies Cross-sectional studies consider relationships between exposure and outcome at a single time point, and are therefore commonly used to describe disease prevalence. By using odds ratios, crosssectional studies can also be used to generate hypotheses about risk factors for disease. This can be made challenging where reverse causality exists, eg in a study considering a possible association between increased body weight and cancer, the tendency for cancer to lead to weight loss may affect results. Figure 5.2 The hierarchy of evidence with the strongest evidence at the top and the weakest at the bottom. An important limitation of cross-sectional data (and other forms of observational study) is that assumptions about individuals are made based on conclusions drawn from a population level. This can lead to a phenomenon termed ‘Simpson’s paradox’, where an association exists in one direction at a population level, but is entirely reversed when subgroups of patients are considered. The most famous example of this is based on data from admissions to the University of California, Berkley in 1973. Overall, 44% of male applicants were admitted, compared with 35% of female applicants, suggesting a gender bias. However, when admissions to the university were broken down by individual department, most actually admitted a greater proportion of female applicants than male. In the final analysis it was noted that male students had applied to less competitive departments, leading to the apparent imbalance. 5.3.4 Case reports Case reports are anecdotal evidence, typically describing events related to a single patient. As such they are placed at the bottom of the hierarchy of evidence. Typically they describe rare events – either details surrounding a rare diagnosis or uncommon features of a common disease. Case reports are prone to publication bias, where only results deemed highly important or statistically significant are submitted, and negative findings are not published. Despite this, case reports are an important means of communicating novel findings. 5.3.5 Ecological studies In ecological studies average values for one or more groups of people are collected. Data of this kind sometimes permit the average incidence rate or prevalence of a given disease to be compared between different populations (eg comparing bowel cancer mortality rates between countries), or within a given population over time (eg bowel cancer mortality rates in a country over a period of decades). Although potentially providing clues about causes of disease, ecological studies are not themselves adequate for testing aetiological hypotheses, primarily because the absence of data on confounders in individuals greatly hampers the ability to control for confounding. The shared and distinguishing characteristics of different study designs are shown in Figure 5.3. 5.4 INTERPRETING RESULTS Results of all studies, whether randomised or observational, should be interpreted in the light of what is already known on the subject and what the latest study can add. Then the clinical and statistical significance of the presented results should be considered. It is rare that a single study can provide a definitive answer, so evidence from many sources must be considered. When doing this, the quality of the evidence must also be considered to allow greater weight to be placed on more credible studies. In the UK, evidence is labelled from A to D, in line with the hierarchy of evidence (Table 5.3). More detailed approaches have been proposed by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group. Table 5.3 Grading of evidence in the UK Grade of Description evidence A B C D Consistent randomised controlled trial and/or cohort study results. Clinical decision rule validated in different populations Consistent retrospective cohort, exploratory cohort, ecological study or case-control study and/or results extrapolated from level A studies Case study or case series and/or extrapolated results from level B studies Expert opinion Figure 5.3 Some shared and distinguishing characteristics of common epidemiological study designs. 5.4.1 Randomised studies Randomised trials must pre-specify outcomes of interest to allow a power calculation to be performed. If a different outcome is assessed at the end of the study, there is no certainty that the study was sufficiently powered to assess this and the validity of the result is less. Equally if a pre-specified outcome is assessed but insufficient patients were recruited to meet the power calculation, then the finding must be considered less reliable. Other issues to consider include the following: Treatment compliance: when patients in a trial do not adhere to the study medication, results may be affected. If equal proportions of patients in each exposure group have poor compliance, then an estimated treatment effect will be harder to detect. If non-compliance is uneven between • groups, then this may over- or understate the treatment effect. Poor compliance may also suggest a high side-effect profile in one group, raising questions about tolerance of a medication, and therefore its real-life use Loss of blinding: a blinded trial protects against bias. Occasionally specific patients need to be • unblinded. Should this occur in a substantial number, then there is a risk of bias having been introduced Intention-to-treat analysis: when patients drop out of a study, cease taking a study drug or move into a different exposure group, results could be altered. In an intention-to-treat analysis, • outcomes for all patients are compared based on their randomly assigned exposure group at the start of the trial. This minimises any confounding that may occur due to deviations from randomisation Subgroup analysis: as subgroups, by definition, comprise a smaller number of patients than the overall study, analyses on these groups have a greater risk for type II error. Subgroup analyses • specified before the study began are more likely to be adequately powered. Analyses designed after the study finished (post hoc analyses) should be interpreted with more caution. 5.4.2 Observational studies The following are key questions when assessing an observational study: Control of confounding: differences in variables between exposure groups should be considered • and (if relevant to the exposure or outcome) adjusted for in the statistical analysis. Where this does not occur the chance of an incorrect result is greater Verification of events: in randomised trials it is common to have an event adjudication committee to review case records and apply a consistent definition for events, eg myocardial • infarction. In cohort studies this is less common, and in retrospective cohort studies almost impossible. This may introduce variability into reported events and hence the results Selection bias: as for case-control studies it is important to consider if it is appropriate to directly compare all patients in cohort studies with each other. If exposure groups are drawn • from two distinct populations, they may systematically differ. Alternatively, if the study is based on a non-random sample of the population, it may not be appropriate to extrapolate the results beyond this patient group (this is the external validity of the study). Due to the potential for error or disagreement to exist in even the best-designed studies, formal approaches for aggregating and comparing the results of studies have been devised. 5.5 SYSTEMATIC REVIEW AND META-ANALYSIS A systematic review of a topic provides a complete summary of all the available literature. First, detailed searches of research databases are performed to locate all potentially relevant papers. These are then reviewed in relation to predetermined selection criteria for inclusion in the review. Published results from all papers selected for inclusion in the review are compared, often by metaanalysis, with the quality of each paper also considered. A meta-analysis typically examines the relationship between a single exploratory and a single outcome variable. Data from two or more studies are pooled to increase patient numbers and therefore the validity of findings. To provide accurate results, all published data must be considered and unpublished data sought. This aims to limit the problem of publication bias and is demonstrated using funnel plots. In these, sample size is plotted against effect size, with a symmetrical funnel shape becoming visible where there is no publication bias. Meta-analysis has the greatest statistical power where individual patient data are used, but can also be performed where only overall study results are available. The Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) groups publish guidelines for the undertaking and reporting of a systematic review or meta-analysis. Although a properly performed systematic review and meta-analysis of multiple randomised studies can be considered the highest level of evidence available, important limitations may exist: • • • • Quality of available data: the quality of a meta-analysis depends upon the quality of available data to pool for analysis. Meta-analysis does not improve or mitigate poor design of original studies: garbage in leads to garbage out! Inappropriate generalisation: although a benefit of meta-analysis is to generalise results over a wider population than is represented in a single study, over generalisation can occur Impact of unpublished data: as discussed above, efforts should be spent to identify all available results to limit publication bias Publication delay: with vast amounts of research being published each month, there is potential for systematic reviews and meta-analyses to be ‘out of date’ by the time of publication. Chapter 6 Gastroenterology CONTENTS 6.1 Anatomy and physiology of the GI tract 6.1.1 Oesophagus 6.1.2 Stomach 6.1.3 Pancreas 6.1.4 Liver 6.1.5 Small intestine 6.1.6 Colon 6.1.7 Gut hormones 6.1.8 Metabolism of haematinics 6.2 Disorders of the mouth, tongue and salivary glands 6.2.1 Mouth ulcers (aphthous ulcers) 6.2.2 Oral manifestations of systemic and dermatological disorders 6.3 Disorders of the oesophagus 6.3.1 Achalasia 6.3.2 Reflux oesophagitis 6.3.3 Other causes of oesophagitis 6.3.4 Barrett’s oesophagus 6.3.5 Oesophageal carcinoma 6.4 Disorders of the stomach 6.4.1 Peptic ulcer disease 6.4.2 Zollinger–Ellison syndrome 6.4.3 Gastric carcinoma 6.4.4 Other gastric pathology 6.4.5 Complications of gastric surgery – dumping syndrome 6.5 Disorders of the pancreas 6.5.1 Acute pancreatitis 6.5.2 Chronic pancreatitis 6.5.3 Pancreatic carcinoma 6.5.4 Endocrine tumours 6.6 Small-bowel disorders 6.6.1 Coeliac disease 6.6.2 Carcinoid tumours 6.6.3 Whipple’s disease 6.6.4 Angiodysplasia 6.7 Nutrition 6.7.1 Assessment of nutritional status 6.7.2 Diarrhoea 6.7.3 Malabsorption 6.8 Large-bowel disorders 6.8.1 Crohn’s disease and ulcerative colitis 6.8.2 Pseudomembranous colitis 6.8.3 Familial polyposis coli 6.8.4 Peutz–Jeghers syndrome 6.8.5 Hereditary non-polyposis colorectal cancer (HNPCC) 6.8.6 Colorectal cancer 6.8.7 Irritable bowel syndrome (IBS) 6.9 Gastrointestinal infections 6.9.1 Gastroenteritis 6.9.2 Gastrointestinal tuberculosis 6.10 Hepatology 6.10.1 Jaundice 6.10.2 Gallstone disease 6.10.3 Ascites 6.10.4 Viral hepatitis 6.10.5 Drug-induced hepatitis 6.10.6 Autoimmune hepatitis 6.10.7 Cirrhosis 6.10.8 Portal hypertension and varices 6.10.9 Hepatic encephalopathy 6.10.10 Primary biliary cirrhosis 6.10.11 Other causes of chronic liver disease 6.10.12 Parasitic infections of the liver 6.10.13 Hepatic abscesses 6.10.14 Hepatobiliary tumours 6.11 Acute abdomen 6.11.1 Investigations of acute abdomen Gastroenterology 6.1 ANATOMY AND PHYSIOLOGY OF THE GI TRACT 6.1.1 Oesophagus The oesophagus is 25 cm long, and is composed of outer longitudinal and inner circular muscle layers. In the upper part these are both striated muscle and in the lower part both are smooth muscle, with the myenteric plexus lying between the two layers. The mucosa is lined with squamous epithelium. The oesophagus is protected from acid damage by a number of defences, including the lower oesophageal sphincter pressure (10–30 mmHg), salivary bicarbonate, oesophageal bicarbonate secretion, gravity and the ‘pinchcock’ effect of the diaphragmatic crura. 6.1.2 Stomach At the gastro-oesophageal junction, the squamous epithelium of the oesophagus changes to columnar epithelium. Secretions total approximately 3 litres per day. In gastric pits, there are chief cells producing pepsin, and parietal cells (fuelled by H+ K+ ATPase) producing hydrochloric acid and intrinsic factor. Mucus and bicarbonate are secreted by surface cells. Innervation is both parasympathetic via the vagus (motor and secretory supply) and sympathetic via Meissner’s and Auerbach’s plexuses. Blood supply is derived from the coeliac trunk. The control of gastric acid secretion is summarised in Figure 6.1 (GIP = gastric inhibitory peptide). Figure 6.1 Control of gastric secretion. 6.1.3 Pancreas Between 1200 ml and 1500 ml of alkaline fluid, containing proteins and electrolytes, is secreted daily. Ninety-eight per cent of the pancreatic mass consists of exocrine acini of epithelial cells; the islets of Langerhans from which endocrine secretion occurs make up the remaining 2%. Innervation is via the coeliac plexus. Pancreatic secretions • • Exocrine (from acini of epithelial cells) • Trypsinogen • Chymotrypsinogen • Pancreatic amylase • Lipase Endocrine (from islets of Langerhans) • Glucagon from α cells • Insulin from cells • Somatostatin from cells • Pancreatic polypeptide 6.1.4 Liver Blood supply is from the hepatic artery and portal vein (bringing blood from the gut and spleen); drainage is via the hepatic vein into the inferior vena cava. Between 250 ml and 1000 ml of bile is produced daily; stimulation of release from the gall bladder is by cholecystokinin. A schema of biliary metabolism is shown in Figure 6.2. 6.1.5 Small intestine This is 2–3 metres in length, with the villi and enterocytes providing a huge surface area that allows the absorption of up to 6 litres daily. The main function of the small intestine is absorption, with most taking place in the duodenum and jejunum. However, it also has an important immune role, with lymphoid aggregates throughout, especially in the form of Peyer’s patches in the ileum. There is secretion of approximately 2 litres of alkaline fluid with mucus and digestive enzymes daily from the enterocytes of the villi, Paneth cells at the bases of the crypts of Lieberkühn and Brunner’s glands. Figure 6.2 Biliary metabolism. Blood supply from the mid-duodenum onwards is derived from the superior mesenteric artery. 6.1.6 Colon This is 90–125 cm in length and its main function is the absorption of water, sodium and chloride. Typically 1–1.5 litres is absorbed daily but in some circumstances this can rise to 5 litres per day. Secretion of mucus, potassium and bicarbonate also takes place. The blood supply is derived from the superior mesenteric artery up to the distal transverse colon; the inferior mesenteric artery supplies the remainder. 6.1.7 Gut hormones The response to a meal is regulated by complex hormonal and neural mechanisms (Table 6.1). Secretion of most hormones is determined by the composition of the intestinal contents. Table 6.1 Major gut hormones Hormone Gastrin Source Stimulus Action G cells in antrum Gastric distension Amino acids in antrum Secretion of pepsin, gastric acid and intrinsic factor Fat, amino acids and peptides in small bowel Pancreatic secretion Gallbladder contraction Delays gastric emptying Cholecystokininpancreozymin Duodenum and jejunum (CCK-PZ) Secretin Duodenum and jejunum Acid in small bowel Pancreatic bicarbonate secretion Delays gastric emptying Motilin Duodenum and jejunum Acid in small bowel Increases motility Vasoactive intestinal Small intestine Neural stimulation Inhibits gastric acid and pepsin secretion peptide (VIP) Stimulates secretion by intestine and pancreas Gastric inhibitory peptide (GIP) Duodenum and jejunum Glucose, fats and amino acids Inhibits gastric acid secretion Stimulates insulin secretion Reduces motility Somatostatin D cells in pancreas Vagal and adrenergic stimulation Inhibits gastric and pancreatic secretion Pancreatic polypeptide PP cells in pancreas Protein-rich meal Inhibition of pancreatic and biliary secretion 6.1.8 Metabolism of haematinics Iron Total body iron is between 4 g and 5 g, with iron content being maintained by control of absorption in the upper small intestine. Most iron intake is in the Fe3+ form, and approximately 5–10% of that consumed is absorbed, which amounts to only 1–2 mg/day. This intake is balanced by identical daily losses through the GI tract, largely resulting from red cell breakdown. Iron is better absorbed from foods of animal than of plant origin. Factors which affect iron absorption • • Increased absorption • Increased erythropoiesis (eg pregnancy) • Decreased body iron (eg GI blood loss) • Vitamin C* • Gastric acid* Decreased absorption • Partial/total gastrectomy • Achlorhydria • Disease of the small intestine (eg Crohn’s disease, coeliac disease) • Drugs (eg desferrioxamine) *Gastric acid and vitamin C promote reduction of Fe3+ to Fe2+ which is more easily absorbed. For a more detailed account of iron metabolism see Chapter 9, Haematology. Folate The usual requirement for this nutrient is approximately 50–200 g/day. It is present in green vegetables. Absorption takes place in the duodenum and jejunum, so deficiency may occur with coeliac disease, Crohn’s disease or any other small-bowel pathology. Dietary folate is converted into 5-methyltetrahydrofolate, which enters the portal blood. Deficiency may also develop if the demands of the body increase, for example in haemolysis, pregnancy and in patients being treated with antimetabolites such as methotrexate. Clinical deficiency results in a macrocytic anaemia, and in pregnancy this can be associated with neural tube defects in the fetus. Vitamin B12 Adults require 1–2 g of dietary vitamin B12 daily. This is predominantly obtained from foods of animal origin. It is tightly protein-bound and is released by peptic digestion. Oral B12 binds to intrinsic factor in the stomach and is then absorbed in the terminal ileum. Deficiency can therefore occur for several reasons: • • • • • Dietary deficiency in vegetarians or vegans Post-gastrectomy (lack of intrinsic factor) Atrophic gastritis (pernicious anaemia) Terminal ileal disease Blind loops Investigations for pernicious anaemia Until 2003, the Schilling test was used to differentiate between deficiency due to terminal ileal malabsorption and lack of intrinsic factor (eg post-gastrectomy, pernicious anaemia), however, this test is no longer available. Gastric parietal cell antibodies, whilst present in the majority of patients, are non-diagnostic. Diagnosis can be confirmed in 50% of cases with serum intrinsic factor antibodies and hypergastrinaemia. In patients with low B12 without intrinsic factor antibodies, intrinsic factor secretion can be measured via nasogastric tube following pentagastrin stimulation (N > 2000 U/h). 6.2 DISORDERS OF THE MOUTH, TONGUE AND SALIVARY GLANDS 6.2.1 Mouth ulcers (aphthous ulcers) Aphthous ulcers can be minor aphthae, major aphthae or herpetiform ulcerations. Minor aphthae are small, cause minimal symptoms, heal within 7–10 days and leave no scar. Major aphthae are larger, heal slowly over a month, occur more frequently and can leave a scar. Herpetiform ulceration is common in elderly females, can be very painful, recurrent, and begins with vesicles and progresses to ulceration. Causes of mouth ulcers • • • • • • • • Inflammatory bowel disease HIV Drugs Malignancy Nutritional deficiency (B12, folate, iron) Behçet’s disease Coeliac disease Sweet syndrome 6.2.2 Oral manifestations of systemic and dermatological disorders The following can cause oral lesions: • • • • • • • • • • • • • • • systemic lupus erythematosus sjögren syndrome inflammatory bowel disease gastro-oesophageal reflux disease sarcoidosis amyloidosis HIV drugs infections Stevens–Johnson syndrome pemphigus vulgaris pemphigoid epidermolysis bullosa acanthosis nigricans lichen planus. 6.3 DISORDERS OF THE OESOPHAGUS 6.3.1 Achalasia Achalasia is a condition of unknown aetiology resulting in abnormal peristalsis and lack of relaxation of the lower oesophageal sphincter. There is a concentric thickening of the muscularis propria layer of the oesophagus. The incidence is approximately 1/100 000 per year, occurring at any age (usually 3rd to 5th decade) but rarely in children. It is demonstrable on manometry, endoscopy or barium studies, where it is characterised by oesophageal dilatation with a smooth distal ‘bird’s beak’ stricture. Chest X-ray may show an air/fluid level behind the heart. Presentation is usually with dysphagia which, unlike other types of stricture, may affect solids and liquids from the outset. Regurgitation, pain and weight loss may occur. There is a risk of recurrent aspiration. Squamous carcinoma is a late and rare complication. Treatment is with endoscopic dilation or surgical myotomy. In some cases, injection of botulinum toxin to the lower oesophageal sphincter may be effective. 6.3.2 Reflux oesophagitis Reflux oesophagitis is an endoscopic diagnosis. Symptoms of acid reflux are extremely common – approximately 40% of Western populations experience ‘heartburn’ at least once per month. The development of reflux oesophagitis depends on a number of factors. Factors predisposing to reflux oesophagitis • • GI factors • Acid/bile content of refluxate • Mucosal defences in oesophagus • Gastric/oesophageal motility • Hiatus hernia Other factors • Obesity • Smoking • Alcohol and coffee intake • Large meals (especially late at night) • Drugs (most commonly theophyllines, nitrates, calcium antagonists and anticholinergics) The correlation between symptoms and endoscopic appearances is poor; severe symptoms are compatible with a normal gastroscopy. The gold standard for diagnosis is 24-hour oesophageal pH monitoring. The advent of impedance pH monitoring also enables the detection of non-acidic reflux events (pH >4), which may be of diagnostic importance, particularly if there is correlation between these episodes and symptoms, enabling differentiation from functional heartburn. The main symptom is heartburn but other symptoms include chest pain, odynophagia (painful swallowing) and dysphagia due to oesophageal dysmotility Complications include strictures, haemorrhage, Barrett’s oesophagus and carcinoma of the • oesophagus (independent of Barrett’s). • Treatment of reflux oesophagitis Treatment is with lifestyle modifications (not evidence-based), antacids, H2 antagonists or proton pump inhibitors. There is currently no evidence for addition of a pro-motility agent (metoclopramide or domperidone) for refractory symptoms. Baclofen has been shown to be effective in reducing reflux events and controlling refractory symptoms, but its use is limited by poor tolerability. Surgery is indicated for patients failing medical therapy, those with large-volume reflux, bile reflux and those preferring to avoid long-term medical therapy. Most fundoplication procedures are now performed laparoscopically, and endoscopic anti-reflux procedures are under evaluation. Patients with functional heartburn (after negative pH impedance studies) may benefit from pain modulator therapies (eg selective serotonin reuptake inhibitors and tricyclic antidepressants). Complications of gastro-oesophageal reflux: • • • • • Barrett’s oesophagus benign oesophageal stricture dental erosions nocturnal asthma laryngitis. 6.3.3 Other causes of oesophagitis Candidal oesophagitis may occur in patients who are immunosuppressed, on antibiotics or steroids (especially inhaled corticosteroids), or suffering from diabetes mellitus. Barium swallow shows irregular filling defects in the oesophagus and white patches can be seen on endoscopy – biopsy will confirm the diagnosis. Chemical oesophagitis may be caused by drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), tetracycline and potassium chloride tablets. Eosinophilic oesophagitis is now an increasingly recognised entity, presenting as dysphagia or with food bolus obstruction. Recognised endoscopic oesophageal abnormalities include: • • • • • rings (trachealisation) longitudinal furrows narrowed calibre felinisation (transient rings) oedema and crêpe paper oesophagus. Diagnosis requires histological finding of the eosinophilic-predominant infiltration of the oesophageal mucosa. The mainstay of treatment is with topical swallowed corticosteroids (eg fluticasone and budesonide, via metered-dose inhalers). Data supporting the use of specific dietary approaches for management of eosinophilic oesophagitis are currently lacking. Herpes simplex virus (HSV) may cause oesophagitis in the immunocompromised. 6.3.4 Barrett’s oesophagus This is found in 10–20% of patients with longstanding acid reflux. It consists of extension of the columnar gastric epithelium into the oesophagus to replace the normal squamous epithelium. It is usually caused by chronic acid exposure, and it is premalignant, although estimates of the rate of transformation to adenocarcinoma vary widely from 30 to 100 times greater than in the normal population. Treatment is of the underlying reflux disease; the benefits of regular endoscopic surveillance and biopsy to detect dysplastic change are controversial, although most centres undertake periodic endoscopy with multiple biopsies to detect evidence of dysplastic change. Photodynamic therapy, argon-beam ablation and endoscopic mucosal resection are being assessed as potential cures. Patients need to receive long-term acid suppression therapy. Hiatus hernia occurs when part of the upper stomach herniates through the diaphragm into the chest and is extremely common, especially with increasing age and obesity. The majority are asymptomatic and found incidentally during investigations. There are two types: • Sliding, 80% – may cause aspiration and acid reflux • Rolling, 20% – may obstruct or strangulate. Hiatus hernia can be diagnosed at endoscopy, by CT scan or with barium studies, and may be seen on a plain chest X-ray. Treatment is symptomatic with acid suppression where necessary. Surgical correction may sometimes be warranted. 6.3.5 Oesophageal carcinoma Oesophageal carcinomas can be squamous or adenocarcinoma. The incidence of the latter is rising rapidly, and adenocarcinomas might soon be the most common oesophageal malignancies. It also increases with advancing age. The squamous tumours arise in the mid-thoracic portion of the oesophagus, while adenocarcinomas arise in the lower oesophagus or on a background of Barrett’s mucosal changes. Risk factors for and clinical features of oesophageal carcinoma • • Risk factors • Smoking • High alcohol intake • Plummer–Vinson syndrome • Achalasia • Barrett’s oesophagus • Chronic reflux (independent of Barrett’s oesophagus) • Chinese or Russian ethnicity • Obesity (for adenocarcinoma) • Tylosis (autosomal dominant palmar and plantar keratosis – very high risk) Clinical features • • • • Pain and dyspepsia Progressive dysphagia for liquids then solids Weight loss Vomiting Oesophageal carcinoma is often asymptomatic until a late stage, resulting in poor survival figures. Diagnosis is usually by endoscopy, allowing biopsy and histological confirmation. Barium swallow typically shows a stricture with irregular shouldering, unlike the smooth outline of a benign peptic stricture. CT scanning is used for staging, particularly for detection of distant metastases, although the accuracy is very poor, especially for lymph node spread; laparoscopy may be useful. Endoscopic ultrasound is especially useful for assessing the locoregional (T and N) staging and is becoming increasingly available. Treatment of oesophageal carcinoma • • • • Surgery • Radical, high operative mortality (up to 10%) • Only a third of lesions are suitable for resection at presentation • Improves 5-year survival to approximately 10% Oesophageal stenting Radical radiotherapy* Chemotherapy* (eg epirubicin, cisplatin, 5-fluorouracil) *Used alone or in combination with surgery. Over 50% of patients have local or distant spread such that palliation is the only option. The overall 5-year survival is less than 10%, but survival is age-related. Those diagnosed at an early stage may be cured by surgery. 6.4. DISORDERS OF THE STOMACH 6.4.1 Peptic ulcer disease Most epidemiological data are from studies predating the rediscovery and treatment of Helicobacter pylori. The incidence rates of peptic ulcer are 0.1–0.3%; the ratio of duodenal to gastric ulceration is 4:1, and males are more susceptible than females. Incidence increases with age and peaks at approximately 60 years of age. Most patients are treated medically with acid suppression and H. pylori eradication, and surgery is limited to those with complications unresponsive to medical or endoscopic therapy. Current NICE guidelines recommend a ‘test and treat’ strategy for the management of dyspepsia. This will heal underlying lesions and avoid the necessity for endoscopy in many cases. Patients with ‘sinister’ symptoms (weight loss, iron deficiency, dysphagia, haematemesis/melaena or an abdominal mass) require urgent endoscopy to exclude gastric and oesophageal malignancy. Peptic ulcer disease • Risk factors • H. pylori colonisation • High alcohol intake • NSAID use • Severe stress • High-dose steroids* • Male sex • Smoking (increases acid, decreases protective prostaglandins) • Zollinger–Ellison syndrome *When combined with NSAIDs. • Clinical symptoms • Epigastric pain (sometimes radiating to the back if a posterior duodenal ulcer) • Vomiting • Symptoms often relapsing/remitting • Weight loss • Iron-deficiency anaemia • Acute haemorrhage** **Duodenal ulcers are the most common cause of upper GI haemorrhage. Causes of upper gastrointestinal haemorrhage • • • Common • Duodenal ulcer – 35% • Gastric ulcer – 20% • Gastric erosions – 18% • Mallory–Weiss tear – 10% 5% or less • Duodenitis • Oesophageal varices • Oesophagitis • Upper GI neoplasia Rare (1% or less) • Angiodysplasia • • • Hereditary haemorrhagic telangiectasia Portal hypertensive gastropathy Aortoduodenal fistula Risk assessment in the management of upper gastrointestinal bleeding The Glasgow–Blatchford score is a useful calculation of risk to identify the urgency of treatment to manage upper gastrointestinal haemorrhage (see Figure 6.3). This score takes into account factors such as blood tests (haemoglobin and urea), physiological parameters (systolic blood pressure and heart rate), presenting symptoms (melaena and syncope) and co-morbidities (hepatic disease and cardiac failure). Helicobacter pylori This Gram-negative spiral bacillus is the primary cause of most peptic ulcer disease. Infection rates increase with age – more than half of those over 50 years of age are colonised by H. pylori in the gastric antral mucosa. H. pylori has been detected in 70% of patients with gastric ulcer and over 90% of patients with duodenal ulcer, compared with 50% of control subjects. Figure 6.3 Management algorithm for upper gastrointestinal hemorrhage (adapted from NICE guidelines: Acute upper gastrointestinal bleeding: management, 2012). Detection of Helicobacter pylori • • • • In patients <55 years of age, without alarm symptoms, non-invasive investigations such as urea breath tests (sensitivity 88–95% and specificity 95%–100%) and stool antigen tests (sensitivity 94% and a specificity of 92%) are recommended. (Malfertheiner et al. Gut 2012;61:646-664 Urea breath test – the patient ingests urea labelled with 14C; CO2, produced by urease, is detected in the exhaled breath Stool antigen testing – detection of Helicobacter antigen by enzyme immunoassay Serology (stays positive after treatment and NOT useful for confirming eradication) In patients requiring endoscopy: • Antral biopsy at endoscopy with haematoxylin/eosin or Giemsa stain Urease testing – the bacillus secretes a urease enzyme which splits urea to release ammonia. A • biopsy sample is put into a jelly containing urea and a pH indicator; this will change colour if H. pylori is present In cases of recurrent H. pylori, culture from antral biopsies may be used to detect antibiotic • sensitivities Proton pump inhibitors should be stopped for 2 weeks before testing by culture, histology, urease test, Urea breath test or stool antigen test. H. pylori causes chronic gastritis and is associated with gastric carcinoma. All symptomatic patients found to be positive should undergo eradication therapy. Effective eradication should be assessed by stool testing (least invasive, cost-effective, highly specific and sensitive), repeat biopsies or breath testing in patients with complications (perforation or haemorrhage) and those with persistent symptoms. Tests to confirm eradication, when indicated, should be performed at least 4 weeks after treatment. Relapse of peptic ulcer disease after H. pylori eradication is less than 5% per year, compared with more than 60% in patients without eradication therapy. Evidence to support eradication of H. pylori in patients with non-ulcer dyspeptic symptoms is mixed, although meta-analysis data suggests that the number needed to be treated to cure one patient is 20. Eradication regimes vary but usually involve triple therapy of a proton pump inhibitor and two antibiotics (eg amoxicillin and clarithromycin); metronidazole resistance is a problem in some areas. 6.4.2 Zollinger–Ellison syndrome This is a rare condition with an incidence of one per million population. Gastrin-secreting adenomas cause severe gastric and/or duodenal ulceration – the tumour is usually pancreatic in origin, although it may arise in the stomach, duodenum or adjacent tissues. Fifty to sixty per cent are malignant; 10% are multiple neoplasms. It may occur as part of the syndrome of multiple endocrine neoplasia type 1, in which case malignancy is more likely. Clinical signs of Zollinger–Ellison syndrome Pain and dyspepsia From multiple ulcers Steatorrhoea • From acid-related inactivation of digestive enzymes and mucosal damage in the upper small bowel Diarrhoea • Due to copious acid secretion • Diagnosis is suggested by very high serum fasting gastrin levels, with little further increase with pentagastrin, and elevated basal gastric acid output. There is a rise in gastrin with secretin (unlike raised gastrin secondary to achlorhydria or proton pump inhibitor (PPI) therapy). Tumour location investigations should include upper GI endoscopy with careful duodenal examination, followed by CT or MR scanning to locate the adenoma and assess for hepatic metastases, although 40% of adenomata are smaller than 1 cm and thus difficult to detect on CT and somatostatin receptor scintigraphy, the best initial test to stage the disease (ENETS consensus guidelines, 2012). If these studies are negative, endoscopic ultrasonography may help in the detection of small lesions (particularly pancreatic gastrinomas). Treatment of Zollinger–Ellison syndrome High-dose acid suppression (eg omeprazole 80–120 mg od) Surgical resection of adenoma • (May be possible) Chemotherapy • (Although poor response) and embolisation may be used for hepatic metastases Somatostatin analogues • To reduce gastric secretion and diarrhoea • The 5-year survival rate is 80% for a single resectable lesion, but falls to 20% if hepatic metastases are present. 6.4.3 Gastric carcinoma The incidence of gastric carcinoma is decreasing in the Western world but it remains one of the commonest causes of cancer deaths. It usually takes the form of an adenocarcinoma, most commonly in the pyloric region; however, the incidence of carcinoma occurring in the cardia is rising. There is very little early detection in the UK, unlike Japan where the extremely high incidence of the disease merits an intensive screening programme. Most patients have local spread at the time of diagnosis, making curative resection unusual. Gastric carcinoma • • Risk factors • Japanese • Hypo/achlorhydria (pernicious anaemia, chronic atrophic gastritis, partial gastrectomy) • Male sex • Dietary factors (high salt, nitrites) • Gastric polyps (rare) Clinical presentation • Dyspepsia (often only symptom) • Epigastric pain • Anorexia and weight loss • Early satiety • Iron-deficiency anaemia • Haematemesis/melaena Very few tumours are confined to the mucosa at diagnosis, when cure rates are above 90%. Overall survival is below 10%. Diagnosis is by endoscopy and biopsy; endoscopic ultrasound and CT scan of the abdomen and thorax are used to determine resectability. Adjuvant chemotherapy before and after surgery may improve prognosis, although patients are often too unwell post-operatively to receive the second course. Other gastric tumours include lymphoma (about 5%), which has a good prognosis, and leiomyosarcoma (<1%), which has a 50% 5-year survival. Gastrointestinal stromal tumours (GIST) are being increasingly identified as incidental lesions as a result of widespread use of imaging and endoscopic investigations. They are submucosal tumours with malignant potential, initially thought to be benign leiomyomas. GIST have a characteristic histological appearance and typical staining with CD117 (CKIT). Treatment is by resection and, if advanced, with chemotherapy. 6.4.4 Other gastric pathology Gastroparesis Reduced gastric motility results in vomiting, bloating and weight loss. Some cases are idiopathic, and others are due to diabetes or autonomic neuropathy, or follow vagotomy. Gastric distension and delayed emptying can be demonstrated using a barium meal (which, along with gastroscopy, is useful to exclude obstructing lesions) or isotope scintigraphy (which is more useful for quantifying the amount of delay). Treatment is with dietary modification and pro-motility agents such as metoclopromide, domperidone or erythromycin, but, if symptoms are severe or if aspiration pneumonia occurs, a feeding jejunostomy may be required. Recent MHRA guidance suggest that domperidone use should be at the lowest effective dose for the shortest possible duration, and avoided in patients with cardiac co-morbidity. Injection of botulinum toxin into the pyloric sphincter may produce temporary symptom improvement in selected patients; however, there is a lack of clear evidence supporting any benefit. Electrical stimulation with gastric pacemakers is currently being evaluated. Ménétrier’s disease This is a very rare condition associated with mucus cell hypertrophy and parietal cell atrophy, mediated by epidermal growth factor. This results in gross thickening of the gastric mucosa, hypochlorhydria and protein-losing enteropathy. Gastric polyps Unlike colonic polyps, gastric polyps are rare and usually benign, occurring in about 2% of the population. Multiple hamartomatous polyps are occasionally found in Peutz–Jeghers syndrome and • adenomata in polyposis coli, but over 90% are hyperplastic (usually arising from Brunner’s glands) • Adenomatous polyps should be removed in view of their premalignant potential. 6.4.5 Complications of gastric surgery – dumping syndrome Gastric surgery is much less common since the advent of H2 antagonists and PPIs, but long-term complications of previous gastric surgery are frequently encountered. Dumping syndrome results from an inappropriate metabolic response to eating and can occur within half an hour of eating (early dumping) or between 1 and 3 hours (late dumping). It occurs in about 20% of patients following gastrectomy/vagotomy. • Symptoms include palpitations, sweating, hypotension and light-headedness • Early dumping is a vagally mediated response to rapid gastric emptying Late dumping is due to hypoglycaemia – a rebound insulin-mediated phenomenon following • transient hyperglycaemia due to a heavy carbohydrate load to the duodenum Diagnosis is usually clinical, but may be confirmed by glucose, electrolyte or blood pressure • monitoring during an attack Treatment is conservative, with small frequent meals with high protein and fat for early dumping • and high carbohydrate for late dumping • Anecdotal reports suggest a benefit from somatostatin analogues (eg Octerotide). 6.5 DISORDERS OF THE PANCREAS 6.5.1 Acute pancreatitis Acute pancreatitis is a common and potentially fatal disease. Mortality in hospital remains at 7–10%, usually due to multi-organ failure or peripancreatic sepsis. Scoring systems, such as the APACHE II, Ranson’s criteria or the Glasgow criteria, aim to identify those patients at high risk by assessing factors such as age, urea, hypoxia and white cell count (WCC), but are unreliable within the first 48 hours. Obstruction of the pancreatic duct by gallstones accounts for over 50% of cases, most of the rest being alcohol-related. Four per cent are thought to have a viral aetiology; all other causes are rare. Oxygen-free radicals are thought to mediate tissue injury. Acute pancreatitis • • • • Causes • Gallstones • Alcohol • Viral (eg mumps, Coxsackie B) • Trauma • Drugs (eg azathioprine, oral contraceptive pill, furosemide, steroids) • Hypercalcaemia • Hypertriglyceridaemia • Ascariasis in tropics • Post-surgery to bile duct/endoscopic retrograde cholangiopancreatography (ERCP) Early complications • Adult respiratory distress syndrome • Acute renal failure • Disseminated intravascular coagulation • Pleural effusions Poor prognostic indicators (Glasgow criteria) • Age 55 >years • WCC >15 × 109 /l • Urea >16 mmol/l • pO2 <8 kPa • Calcium <2 mmol/l • Albumin <32 g/l • Glucose >10 mmol/l • Lactate dehydrogenase (LDH) >600 IU/l • Aspartate aminotransferase (AST) >200 IU/l • (Severe attack if more than three factors are present within 48 hours) Late complications • Splenic or portal vein thrombosis • Pseudocyst • Abscess Clinical presentation is usually with severe epigastric pain, radiating to the back and vomiting, with tachycardia and hypotension in more severe cases. Amylase (in blood, urine or peritoneal fluid) is raised, usually to at least four times normal values. A plain abdominal X-ray may show a sentinel loop of adynamic small bowel adjacent to the pancreas. Treatment is supportive, with fluids and analgesia; the presence of three or more poor prognostic indicators suggests that referral to ITU should be considered. Routine use of prophylactic antibiotics in severe pancreatitis are not recommended and should only be used to treat extra pancreatic infection or infected necrosis (American College of Gastroenterology guidelines, 2013). In severe pancreatitis due to gallstones (where jaundice and cholangitis are present), early ERCP to achieve duct decompression is of proven value. Any patient with a biliary cause should have cholecystectomy during the same admission once the acute symptoms have settled. 6.5.2 Chronic pancreatitis Chronic pancreatitis is an inflammatory condition characterised by irreversible damage to the exocrine and later to the endocrine tissue of the pancreas. Most cases are secondary to alcohol, but it is occasionally due to cystic fibrosis. There is a male predominance, often with a long history of alcohol abuse. Chronic pancreatitis • • Clinical signs • Malabsorption and steatorrhoea • Abdominal pain radiating to the back, often severe and relapsing • Diabetes mellitus Diagnosis • X-ray may show speckled calcification, present in 50–60% of advanced cases • CT is the most sensitive for detection of pancreatic calcification ERCP shows irregular dilatation and stricturing of the pancreatic ducts, although magnetic • resonance cholangiopancreatography (MRCP) is now the modality of choice for diagnostic pancreatography Endoscopic ultrasonography has emerged as being sensitive and accurate for diagnosing • early and late changes of chronic pancreatitis Pancreolauryl and PABA (p-aminobenzoic acid) testing are of use to assess exocrine • function – both these involve ingestion of an oral substrate which is cleaved by pancreatic enzymes and can then be assayed in the urine The faecal elastase test is increasingly used for detecting exocrine insufficiency and is more • acceptable to patients • An oral glucose tolerance test can be used to diagnose early glucose intolerance Treatment is with abstention from alcohol, pancreatic enzyme supplementation, analgesia and insulin to treat diabetes. Antioxidants (vitamins A, C and E) are of unproved value, and coeliac axis block for pain relief is now rarely performed because of poor results and surgical complications. Sixty per cent survive for 20 years – death is usually from complications of diabetes or alcohol. 6.5.3 Pancreatic carcinoma Carcinoma of the exocrine pancreas is responsible for more than 6000 deaths per year in the UK, with an incidence of 110–120 per million, rising to 800–1000 per million over the age of 75 years. Seventy to eighty per cent arise in the head of the pancreas where there is maximal pancreatic tissue; those in the tail are often silent in the early stages and present at an advanced stage. Pancreatic carcinoma may invade the common bile duct causing obstructive jaundice and the typical ‘double duct sign’ at ERCP. It can also invade the duodenum, leading to small-bowel obstruction. • • • • • • The risk is increased 2–3-fold in smokers, and also possibly in those with diabetes, although it has been suggested this is an early symptom of carcinoma rather than a risk factor. Alcohol does not increase the risk Clinical signs include abdominal pain radiating through to the back, weight loss and obstructive jaundice in 80–90%. The exocrine and endocrine functions are usually maintained Ultrasound and pancreatic protocol CT is used to detect any distant metastases Endoscopic ultrasound is useful for locoregional staging and allows histological diagnosis via fine-needle aspiration ERCP with a view to bile duct stenting is probably of most use in relieving jaundice and pruritus CA-19.9 is released from exocrine pancreatic cancer cells, and baseline levels may guide treatment and follow-up and have prognostic significance. Between 10% and 20% of patients are suitable for surgery but perioperative mortality is high. The only curative treatment of pancreatic cancer is radical surgical treatment, so accurate staging to determine resectability is critical. If unresectable, the goals of treatment are to optimise local control, control metastatic growth, prolong survival and palliate symptoms. Novel techniques such as intraoperative radiotherapy and irreversible electroporation (soft tissue ablation using ultra short, strong electrical fields) are experimental and not currently recommended in routine clinical practice for unresectable disease. For metastatic disease, gemcitabine or combination chemotherapy (5-FU, irinotecan and oxaliplatin) are considered first-line options, and median survival can be improved from 2–3 months from diagnosis, to 6 and 11 months, respectively, using these regimens. However, the overall 1- and 5-year survival rates remain poor. 6.5.4 Endocrine tumours These are very rare, with an annual incidence of 4 per million, but they are incidentally detected at post-mortem. They can occur independently, or as part of multiple endocrine neoplasia (MEN-1) syndrome. The more important lesions include: • • • • • insulinoma gastrinoma (Zollinger–Ellison syndrome, see Section 6.4.2) glucagonoma VIPoma somatostatinoma. Insulinoma These arise from the islets of Langerhans and often present with unusual symptoms (visual disturbances, irritability, abnormal behaviour, confusion, amnesia, paraesthesiae and drowsiness) after an overnight fast or before meals as a result of hypoglycaemia. Patients often discover that glucose is helpful and may go for years without diagnosis. Glucagonoma These tumours arise from α cells of the pancreas and present clinically with a characteristic rash (migratory necrolytic erythema), weight loss, glucose intolerance or frank diabetes, and anaemia. Tumours are often very large at diagnosis and are usually malignant. VIPoma Excessive VIP (vasoactive intestinal polypeptide) produces an extreme secretory diarrhoea (usually >3 litres per day) resulting in hypochlorhydria and hypokalaemia. Somatostatinoma This rare tumour produces a syndrome of diabetes mellitus, diarrhoea, gallbladder disease, weight loss, steatorrhoea and hypochlorhydria due to inhibition of insulin and pancreatic enzymes. 6.6 SMALL-BOWEL DISORDERS The small bowel is the main site of absorption of nutrients for the body, so small-bowel diseases such as coeliac disease or Crohn’s disease often result in malabsorption and malnutrition. Small-bowel pathology can be difficult to diagnose because of the inaccessibility of this part of the GI tract. Small-bowel enteroscopy may be of use in addition to tests such as gastroduodenoscopy or barium studies. CT/MR enterography and wireless capsule endoscopy are increasingly being used. 6.6.1 Coeliac disease Also known as gluten-sensitive enteropathy, this common and under diagnosed condition is caused by an immunological reaction to the gliadin fraction of wheat and other cereals. Some 0.1–0.2% of the population are affected and the onset may be at any age, although peaks occur in babies and in the third decade. The incidence is greatly increased in western Ireland, and it has been postulated that this is due to increased reliance on potatoes rather than wheat products as a source of carbohydrate. Thus those affected with gluten intolerance continued to thrive and reproduce. HLA-B8, DRw3 is present in 90%. Pathologically, gliadin provokes an inflammatory response which results in partial or total villous atrophy in the proximal small bowel; this reverses on a gluten-free diet but recurs on rechallenge. Coeliac disease • • • Clinical picture • Diarrhoea • Oral aphthous ulcers • Weight loss • Growth retardation • General malaise • Neurological symptoms – ataxia, weakness and paraesthesiae • Abdominal pain • Amenorrhoea Complications • Anaemia–folate, B12 or iron deficiency • Increased malignancy* • Hyposplenism • Dermatitis herpetiformis – itchy rash, improves with dapsone • Osteomalacia • Abnormal liver function tests Diagnosis • Anti-endomysial/Anti-tissue transglutaminase antibodies *There is an increased risk of all GI malignancies but especially small-bowel lymphoma, occurring in approximately 6% of cases. This risk returns to almost normal with treatment of the disease. Treatment is by strict avoidance of wheat, rye and barley. The role of oats is debatable, and many patients can eat oats without significant pathological or clinical effects. Patients require folate, iron and calcium supplements in the early stages of treatment. Failure to respond to treatment is usually due to non-compliance with diet (often unwittingly), but the possibility of supervening pathology, such as lymphoma, should always be excluded. A small number of patients with refractory coeliac disease may require steroids to control their symptoms. Although 10% of first-degree relatives will develop coeliac disease, routine screening is not advocated unless they have symptoms to suggest the diagnosis. Other causes of villous atrophy: • Whipple’s disease • Hypogammaglobulinaemia • Lymphoma • Giardiasis • Cow’s milk protein intolerance Tropical sprue: aetiology unknown, but likely to be infective as it responds to long-term • tetracycline therapy Collagenous sprue: rare small-bowel disorder with villous atrophy and subepthelial collagen • deposition histologically. Often non-responsive to gluten-free diet. 6.6.2 Carcinoid tumours These are relatively common; it is estimated that carcinoid tumours are an incidental finding in up to 1% of post-mortems. Carcinoid syndrome, however, is extremely rare. Carcinoid tumours arise from the enterochromaffin cells of intestinal mucosa (neuroendocrine cells found in the lamina propria) throughout the gut. The most common GI sites are the appendix (from which site metastasis is rare) and the ileum. The tumours secrete serotonin and therefore can be detected by assay of the metabolite 5hydroxyindoleacetic acid (5-HIAA) in the urine Serotonin causes bronchoconstriction and increased gut motility, resulting in the symptoms • documented below • Histamine and adrenocorticotrophin may also be synthesised Carcinoid syndrome occurs only when secondaries in the liver release serotonin into the • systemic circulation; any hormone from non-metastatic gut carcinoids will be metabolised in the liver. • Clinical features of carcinoid syndrome • • • • Diarrhoea Bronchospasm Local effect of the primary (eg obstruction, intussusception) Flushing Right heart valvular stenosis (left heart may be affected in bronchial carcinoid or if an atrial • septal defect (ASD) is present) Treatment depends on the site of the primary and presence of metastases. Many carcinoids are very slow growing, with patient survival of more than 20 years. With widespread metastases 5• year survival varies from zero to 25%, the better figures reflecting the less aggressive nature of appendiceal primaries Treatment of carcinoid tumours and syndromes • Surgical resection • Good prognosis if no metastases • • • Octreotide, methysergide and cyproheptadine • For diarrhoea Resection or embolisation • Of hepatic metastases Phenoxybenzamine • For flushing Carcinoid tumours may occasionally cause pellagra due to tumour uptake of tryptophan (the precursor of nicotinic acid). 6.6.3 Whipple’s disease This is an uncommon condition usually affecting middle-aged men (occasionally women and children) caused by infection with the Gram-positive actinobacteria, Tropheryma whippelei. Jejunal biopsy shows deposition of macrophages containing PAS-positive granules within villi. Clinical features include abdominal pain, weight loss, diarrhoea, and arthropathy. The central nervous system can be involved in later stages, characterised by cognitive function abnormalities, as well as oculomasticatory and oculofacioskeletal myorhythmia (rhythmic movements of masticatory and other skeletal muscles synchronised with ocular movements). Whipple’s endocarditis can also occur. Whipple’s disease remains poorly understood but symptoms respond to extended courses of tetracycline or penicillin. 6.6.4 Angiodysplasia Although most commonly occurring in the caecum and ascending colon, angiodysplasia is included here because of the diagnostic challenge it may present when present in the small intestine. Angiodysplasia can be found throughout the GI tract and its frequency in the population is unknown. It is an uncommon but significant cause of acute gastrointestinal haemorrhage, but presents more frequently as occult iron-deficiency anaemia. Diagnosis of angiodysplasia This can be difficult, but useful investigations include: • Gastroscopy/colonoscopy: may detect gastric and large-bowel lesions Mesenteric angiography: only of use if currently bleeding; if so, will locate source in • approximately 40% Small-bowel enteroscopy: intubation of the upper small bowel is possible using an elongated • endoscope with an overtube to provide rigidity Capsule enteroscopy: this is the most effective method of detecting small-bowel angiodysplasia and other sources of small-bowel bleeding. A small (11 × 27 mm) capsule is swallowed which • transmits thousands of images from the gut as it transits. Images are analysed manually and with computer assistance. Typical capsule transit times are: oesophagus 1–4 seconds, stomach 22–48 minutes and small bowel around 4 hours. The main risk that patients should be informed about before consenting to capsule enteroscopy is capsule retention (capsule remaining in the digestive tract for at least 2 weeks, sometimes requiring medical, endoscopic or surgical removal). In the general population the risk of capsule retention is quoted as 1.4-2.5%. For this reason, capsule enteroscopy should not be performed in patients with obstructive symptoms and/or radiological evidence of intestinal obstruction. Patients with smallbowel Crohn’s disease, those taking high doses of nonsteroidal anti-inflammatory drugs and those with abdominal radiation injury are at higher risk of capsule retention. Such patients may benefit from an examination using an M2A (lactose-filled) patency capsule, which is designed to dissolve when impacted in stenosed bowel. Treatment of angiodysplasia Treatment is by argon plasma photocoagulation at endoscopy, or by embolisation of the bleeding point during angiography. Second-line treatment with Thalidomide and/or Octreotide has been shown to achieve clinically meaningful responses in patients that are refractory or unsuitable for other interventions. Surgery may be indicated if the lesions are very numerous or if there is severe bleeding. Patients need to receive long-term iron supplementation. Hormonal treatment with oestrogen (± progesterone) has been tried with poor results. 6.7 NUTRITION 6.7.1 Assessment of nutritional status In practice, nutritional assessment should be based on a pragmatic approach using a combination of history, examination and blood tests to identify specific nutrient deficiencies. The following assessments help evaluate nutritional status and risk: • • • • Reported recent weight loss Dietary assessment: food diary Behavioural patterns to food intake Body mass index (BMI): weight in kilograms/(height in metres)2 Biochemical markers: renal profile, electrolytes (magnesium, phosphate and potassium), albumin • (unreliable – often normal in severe malnutrition and affected by inflammation and synthetic liver function), C-reactive protein (CRP), glucose and HbA1c (glycated haemoglobin) Given that around a third of hospitalised patients are at risk of malnutrition, and provision of good nutritional status improves clinical outcomes, NICE recommends that all patients admitted to hospital should be screened for risk of malnutrition using a validated screening tool. The British Association of Parenteral and Enteral Nutrition (BAPEN) has developed the Malnutrition Universal Screening Tool (MUST) which is widely used for this purpose. Using this tool, the overall risk of malnutrition is calculated based on the BMI, the percentage of unintentional weight loss over a 3- to 6-month period and whether the patient has had, or is likely to have had, no nutritional intake for more than 5 days. The maintenance of adequate nutrition requires three main criteria to be fulfilled: Intact GI tract This may be compromised by resections resulting in a short-bowel syndrome, or by fistulae such 1. that segments of bowel are bypassed. As different nutrients are absorbed from different parts of the gut, a variety of clinical sequelae may occur depending on the segment of bowel affected (eg vitamin B12 deficiency after terminal ileal resection, iron deficiency after partial gastrectomy) Ability to absorb nutrients Impairment of absorptive function may be caused by mucosal damage as occurs in Crohn’s or 2. coeliac disease, or after radiation damage. Motility problems resulting in accelerated transit times may reduce absorption Adequate intake 3. This depends on both the motivation to maintain an adequate oral intake, often lacking in sick and elderly patients, and on the composition of the diet. An inability to maintain nutrition is an indication to provide supplementation by one of three routes listed below. The underlying disease will determine which is appropriate: Oral: obviously the most simple form but relies on a conscious patient with an intact swallowing • mechanism. High-protein or -carbohydrate drinks may be used to provide good nutritional intake in a small volume Enteral: useful when swallowing impaired (eg in neurological disease) or when high-volume intake is needed. May take the form of a simple nasogastric tube, or a percutaneous gastrostomy • (PEG) or jejunostomy, which can be inserted endoscopically, radiologically or surgically. Can be for short- or long-term supplementation Parenteral: this is intravenous feeding, either to supplement enteral nutrition or to provide total • support in the case of complete intestinal failure. Refeeding syndrome When re-establishing feeding (orally, enterally or parenterally) in malnourished patients with inadequate oral intake for more than 5 days, it is important to recognise the high risk of refeeding syndrome. Overenthusiastic feeding of these patients can precipitate surges in insulin levels, which in turn provoke large intracellular shifts in potassium, phosphate and magnesium, leading to low plasma levels of these ions. Potential serious adverse clinical consequences of these preventable electrolyte deficiencies include: • • • • • • • cardiac instability/arrhythmias and sudden death seizures delirium paraesthesia myopathy haemolysis paralysis • oedema • respiratory and cardiac failure. A cautious approach to refeeding is therefore paramount, gradually increasing calorie intake and correcting electrolyte deficiencies. It is mandatory to monitor serum electrolytes (including potassium, phosphate, magnesium and calcium) daily in this situation. Also, during refeeding there is increased consumption of thiamine by cells, so at-risk patients should also receive thiamine replacement before starting nutritional support (oral, enteral or parenteral) as prophylaxis for Wernicke’s encephalopathy. Problems with parenteral nutrition • Central venous access needed Patient/carer must be sufficiently motivated and competent to master aseptic techniques and care • for venous line Electrolyte abnormalities may occur – need for careful monitoring; also need to monitor trace • elements such as zinc and selenium • Risk of sepsis – central venous catheter infections, right heart endocarditis Examples of specific nutritional deficiencies are covered in Chapter 13, Metabolic Diseases. 6.7.2 Diarrhoea Diarrhoea means different things to different people but medically is defined as >200 ml of stool per day. In lay terms, diarrhoea is used to describe increased frequency and/or decreased consistency of motions. There are several causes (as illustrated below), and these result in diarrhoea by differing mechanisms. Various classifications can be used: • Acute or chronic • Large bowel (often smaller amounts, may contain blood or mucus) • Small bowel (often voluminous, pale and fatty). Causes of diarrhoea • • Osmotic (osmotic agents draw water into the gut) • Osmotic laxatives (lactulose, polyethylene glycol) • Magnesium sulphate • Lactase deficiency* (poorly absorbed lactose acts as a laxative) • Stops with fasting Secretory (failure of active ion absorption ± active ion secretion) Infection (eg Escherichia coli, cholera) Malabsorption Bile salts (↑ deposition into bowel after cholecystectomy) Continues with fasting, nocturnal, high volume (> 1 l/day) Stool electrolytes and osmotic gap can be used to differentiate between secretory and • osmotic diarrhoeas Altered motility (altered peristalsis or damage to autonomic nervous system) • Irritable bowel syndrome • Thyrotoxicosis • Post-vagotomy • Diabetic autonomic neuropathy • Stops with fasting • • • • • *Lactase deficiency may be congenital (possibly severe) or acquired, and often occurs in the setting of viral gastroenteritis or coeliac disease. Complete exclusion of lactose from the diet is usually not necessary – there is often a threshold below which symptoms are absent. Causes of bloody diarrhoea • • • • • • • • • • • Ulcerative colitis Crohn’s disease Colorectal cancer Ischaemic colitis Pseudomembranous colitis Schistosomiasis Salmonella Shigella Amoebiasis Campylobacter Strongyloides stercoralis Haemolytic uraemic syndrome (which can be caused by E. coli type O157, Campylobacter, • Shigella, etc) Investigations for diarrhoea History and examination vital, including rectal examination • History may be suggestive of large- or small-bowel cause; examination per rectum to exclude overflow or rectal tumour • Gut hormone assay • Sigmoidoscopy/colonoscopy If large-bowel cause suspected B12, folate, and iron assay • If small-bowel cause suspected Gastroscopy • With duodenal biopsy if small-bowel cause suspected Biochemistry • Electrolyte disturbance: include thyroid function tests, albumin and calcium Stool examination • Including examination for ova, cysts and parasites, and laxative screen SeHCAT (selenium-75 homotaurocholic acid retention) test for bile salt malabsorption. This is a • radiolabelled isotope scan for measuring bile acid loss from enterohepatic circulation Faecal elastase • If pancreatic exocrine insufficiency suspected Small-bowel radiology • If small-bowel cause suspected Urine analysis • Laxative screen 5-HIAA Hydrogen breath test Bacterial overgrowth in the small bowel can be identified by detection of exhaled hydrogen from • ingested glucose or lactulose. False positives occur with rapid small-bowel transit that results in prolonged hydrogen release Serology • Anti-endomysial antibody Faecal calprotectin Faecal calprotectin is a highly specific (96%) and sensitive (93%) screening test in patients with chronic diarrhoea, to exclude inflammatory bowel disease and support a diagnosis of irritable bowel syndrome (IBS) in patients with chronic lower gastrointestinal symptoms in whom cancer • is not suspected. If there is no suspicion of malignancy, then faecal calprotectin, where available, can be considered as an initial investigation of choice where the results can inform the physician about the need for further (more invasive) investigations such as sigmoidoscopy or colonoscopy. (Van Rheenan et al. 2010) There is currently still some uncertainty as to appropriate cut-off levels and appropriate age range for use of this test. Treatment of diarrhoea This depends on the underlying disease process, which should be treated if possible. Loperamide or codeine increases gut transit time and so may control symptoms. Similarly, racecadotril, an oral enkephalinase inhibitor, reduces hypersecretion of water and electrolytes into the intestinal lumen and is now licensed in the UK for symptomatic treatment of acute diarrhoea in adults. This drug has effects comparable to loperamide but without the adverse effects such as constipation and abdominal distension. Octreotide may be useful for chronic secretory diarrhoea, short-bowel symptoms and diarrhoea secondary to endocrine tumours. Cholestyramine can be useful in bile salt malabsorption 6.7.3 Malabsorption Malabsorption may be defined as a failure to absorb sufficient exogenous nutrients or to reabsorb endogenous substances such as bile salts. It may be caused by several factors, because normal absorption depends on gut structure, motility and secretion of hormones and enzymes. Malabsorption usually results in diarrhoea. Clinical presentation depends on the type and site of defect, and includes weight loss and general ill health, osteomalacia, or specific nutritional deficiencies such as of B12 and folate. Investigation of malabsorption Investigation is as for diarrhoea. In addition, specific tests for malabsorption include: Xylose absorption test: 25 g of xylose is given orally. Urinary excretion of xylose is quantified. More than 20% should appear in the urine if small-bowel absorption is normal • Pancreatic function testing: see Section 6.5 • • 14 C breath testing: to detect overgrowth (although the most accurate test remains quantitative bacteriological assay of jejunal aspirates) Causes of malabsorption • • • Structural abnormalities • Coeliac disease* • Crohn’s disease* • Post-surgical resections* • Bacterial overgrowth due to blind loops or anatomical abnormalities • Whipple’s disease • Tropical sprue Motility abnormalities • Thyrotoxicosis • Drugs (eg neomycin) • Diabetes Secretory abnormalities • Gl tract infection (eg Giardia, amoebiasis) • Chronic pancreatitis* • Cystic fibrosis *Common causes in the UK. Bacterial overgrowth of the small bowel This is common in patients who have undergone small-bowel resections or in those with jejunal diverticulae or systemic sclerosis. These bacteria are able to metabolise vitamin B12 and carbohydrate, but the serum folate usually remains normal or elevated. Patients usually have diarrhoea, and malabsorption may ensue. Treatment is with antibiotics such as metronidazole, tetracycline or ciprofloxacin, and recurrent courses of these antibiotics may be necessary. 6.8 LARGE-BOWEL DISORDERS 6.8.1 Crohn’s disease and ulcerative colitis Crohn’s disease and ulcerative colitis are both chronic relapsing inflammatory diseases of the gastrointestinal tract. Aetiology of inflammatory bowel disease There is an undoubted genetic predisposition based on the identification of at least five susceptibility loci in family studies, and the recent discovery of the NOD2/CARD15 gene on chromosome 16 which is clearly associated with the development of Crohn’s disease. This gene codes for a protein which facilitates opsonisation of gut bacteria, and animal studies have confirmed that colitis does not develop in animals raised in a sterile environment. Putative infectious agents including Mycobacterium paratuberculosis have not been confirmed, and recent speculation about the role of measles or the measles vaccination in Crohn’s disease has no epidemiological basis. The use of NSAIDs and the oral contraceptive pill have also been implicated, but mechanisms remain unclear. The major similarities and differences between the two diseases are detailed in Table 6.2. Treatment of inflammatory bowel disease (IBD) Treatment is similar for both Crohn’s disease and ulcerative colitis. Here we discuss the major treatment strategies and important differences between ulcerative colitis and Crohn’s Disease management. 5-aminosalicylic acid (5-ASA) compounds (mesalazine, olsalazine, balsalazide): these are used to treat mild-to-moderate relapses of ulcerative colitis and are taken long term to maintain remission. Oral 5-ASAs are targeted to the colon using pH-dependent or bacterial cleavage systems to release active 5-ASA from carrier molecules. Side-effects are common with sulfasalazine, and these include rash, infertility, agranulocytosis, headache, diarrhoea and renal • failure. Interstitial nephritis is a rare side-effect of all 5-ASA drugs. Based on disease extent, patients with endoscopically confirmed distal colitis (inflammation only below the descending colon) may benefit from topical 5-ASA preparations via retention enemas and or suppositories. In contrast to ulcerative colitis, there is no evidence to support the use of 5-ASA drugs in Crohn’s disease, either in maintenance or active disease Table 6.2 Clinico-pathology of Crohn’s disease and ulcerative colitis Crohn’s disease Ulcerative colitis Affects any part of the Gl tract from Always involves the rectum and extends mouth to anus. Commonly terminal confluently into the colon. Terminal ileum ileum (70%), colon (30%), anorectum may be affected by ‘backwash ileitis’, but (30%). May be ‘skip lesions’ of normal remainder of the gut unaffected mucosa between affected areas Pathology Transmural inflammation Mucosal ulcers (in 30% only) Fissuring ulcers Lymphoid aggregates Neutrophil infiltrates Clinical Abdominal pain prominent and frequent fever Diarrhoea, often with blood and mucus Diarrhoea blood per rectum Fever Anal/perianal/oral lesions Abdominal pain less prominent Stricturing common, resulting in obstructive symptoms Associations Increased incidence in smokers (50– 60% smokers) Skin disorders: Erythema nodosum (5–10%) Pyoderma gangrenosum (0.5%) Iritis/uveitis (3–10%) Joint pain/arthritis (6–12%) Cholelithiasis (common) Primary sclerosing cholangitis Clubbing Depression Diagnosis Faecal calprotectin (raised) Ileocolonoscopy with biopsies: Cobblestoning of mucosa Rose-thorn ulcers Strictures Skip lesions Terminal Ileitis OGD (if upper GI symptoms) CT/MR enterography: assess smallbowel involvement Mucosa and submucosa only involved Inflammatory cell infiltrate Crypt abscesses Decreased incidence in smokers (70–80% non-smokers) Increased incidence of: Primary biliary cirrhosis Chronic active hepatitis Sclerosing cholangitis Other systemic manifestations occur but less common than in Crohn’s disease Faecal calprotectin (raised) Sigmoidoscopy (often initially) or colonoscopy (often later) with biopsies: Determine anatomical extent of colitis Determine disease activity - Mayo endoscopic score is widely used to describe mucosal appearances Mayo endoscopic score (ulcerative colitis): 0 = inactive (normal) 1 = mild (erythema, decreased vascular pattern, mild friability) 2 = moderate (marked erythema, absent vascular pattern, friability, erosions) 3 = severe (spontaneous bleeding, ulceration) Fistulae: Entero-enteral Entero-vesical Entero-vaginal Perianal Carcinoma – slightly increased risk of Complications colonic malignancy (see later)* B12 deficiency common (decreased absorption in terminal ileal disease) Iron deficiency anaemia Abscess formation Venous thromboembolism Fistulae do not develop Toxic megacolon (uncommon – usually an indication for urgent colectomy) Increased risk of carcinoma* (risk increases with time since diagnosis, extent of disease and early age of onset) Iron-deficiency anaemia Venous thromboembolism *See section ‘Carcinoma complicating inflammatory bowel disease’. • • • • • • Steroids: this is the main treatment for active disease, and is available for topical, oral and intravenous administration. Terminal ileal Crohn’s disease may be treated with topically acting oral budesonide, which is metabolised in the liver and has far fewer systemic side-effects. The use of steroids should be minimised to short tapering regimes to induce remission, and calcium and vitamin D supplementation should be co-prescribed Immunosuppressants: azathioprine or mercaptopurine are very effective as steroid-sparing agents in steroid refractory cases, those requiring frequent steroid courses for exacerbations or patients unable to wean off steroids. Their use as a monotherapy for active disease is limited by their slow onset of action. Their use is limited by gastrointestinal and systemic side-effects, and close monitoring for evidence of marrow suppression and hepatotoxicity is necessary. Pancreatitis is an uncommon but potentially serious idiosyncratic side-effect. Methotrexate is useful in patients with Crohn’s disease but does not appear to be effective in patients with ulcerative colitis. Intravenous ciclosporin is sometimes effective in the treatment of acute, steroid-resistant colitis, but long-term benefit has not been established Metronidazole and ciprofloxacin, used in the treatment of perianal Crohn’s disease Anti-tumour necrosis factor-α (biologics): infliximab (chimeric [mouse/human] monoclonal antibody) and adalimumab (recombinant human IgG1 monoclonal antibody against TNF-α) are recommended by NICE in the treatment of severe active Crohn’s disease refractory to conventional therapy (immunosuppressants and corticosteroids), or when conventional therapy is not tolerated/ contraindicated. A planned course is recommended until treatment failure (including the need for surgery) or 12 months, at which point disease activity should be reassessed to guide further management. Adalimumab can be administered subcutaneously. Infliximab is also recommended for fistulising Crohn’s disease refractory to antibiotics, drainage and immunosuppression Nutritional support and treatment: patients with inflammatory bowel disease are often malnourished and require nutritional supplementation (enteral or parenteral), especially if • surgery is planned. An elemental or polymeric diet may be as effective as steroids in inducing remission in Crohn’s disease Surgery: surgical resection is very effective for symptom relief in obstructive Crohn’s disease, and colectomy offers a cure to patients with ulcerative colitis. Absolute indications for surgery in ulcerative colitis are exsanguinating hemorrhage, perforation and documented or strongly suspected carcinoma. Other indications for surgery are severe colitis with or without toxic megacolon unresponsive to conventional maximal medical therapy, and less severe but medically • intractable symptoms or intolerable medication side-effects (ACG guidelines, 2010). The recurrence rate for Crohn’s disease after surgery is approximately 50%. The role of postoperative medication (azathioprine, anti-TNF) in reducing risk of recurrence is being evaluated and debated. Current opinion is that treatment should be risk-stratified and given to those deemed to have high risk of recurrence. Ileoanal pouch surgery restores continence to patients undergoing colectomy Immunisation: recent literature has highlighted that patients with inflammatory bowel disease are vulnerable to infections secondary to immunocompromise, both from the disease itself and potent immunosuppressive medications which they may be taking or may require in the future. It is therefore important that at the time of diagnosis of inflammatory bowel disease, immunity and • serologic status should be determined and detailed vaccination history should be taken. Patients with inflammatory bowel disease should be recommended to recieve the following vaccinations: varicella, human papilloma virus, influenza, pneumococcal and hepatitis B vaccine. However, patients already on immunosuppresants or biological drugs and those with human immunodeficiency virus should avoid live-virus vaccines. Management of acute severe colitis • • • • • • • • • Defined by Truelove and Witts’ criteria, more than six bloody stools/day PLUS one sign of systemic toxicity: heart rate >90/min, temperature >37.8°C, Hb <10.5 g/dl or ESR >30 mm/hr Exclude infective cause (stool cultures) Accurate recording of stool frequency (stool chart) Intravenous steroids 5-days, fluid and electrolyte replacement Prophylactic thromboprophylaxis Daily abdominal examination ± abdominal radiographs/ bloods (including inflammatory markers) Consider urgent flexible sigmoidoscopy (without bowel preparation) Colectomy rate relatively high – 30%; early surgical consultation and daily joint review with gastroenterologist is important Day 3: if no improvement: – consider surgery or ‘rescue’ medical therapy (ciclosporin/ infliximab) – stool frequency 8/day or CRP >45 predictor of colectomy in 85% cases Colon diameter >5.5 cm (on abdominal radiograph) needs surgical referral. Carcinoma complicating inflammatory bowel disease The risk of carcinoma associated with inflammatory bowel disease is increased if: • • • • • Onset of IBD occurs at less than 15 years of age Disease duration has been longer than 10 years There is widespread disease (eg total colitis) The disease takes an unremitting course Compliance with treatment and follow-up is poor. Colonoscopic surveillance for inflammatory bowel disease Current NICE guidelines (published March 2011) state that the risk of developing colorectal cancer for people with ulcerative colitis is estimated as 2% after 10 years, 8% after 20 years and 18% after 30 years of disease. The risk of developing colorectal cancer for people with Crohn’s disease is considered to be similar to that for people with ulcerative colitis with the same extent of colonic involvement. • • • • • Therefore patients with both Crohn’s disease and ulcerative colitis are recommended to have an index surveillance colonoscopy 8-10 years after the onset of symptoms to assess disease extent and other endoscopic risk factors. Pancolonic dye spraying (chromoendoscopy) with targeted biopsies of abnormal areas is recommended. If chromoendoscopy is not used, two to four random biopsy specimens should be taken every 10 cm from the entire colon, with additional samples of suspicious areas The interval for surveillance colonoscopy depends on disease extent, duration, histology and additional risk factors Low-risk patients (extensive colitis with no active endoscopic or histological inflammation, left-sided colitis or Crohn’s colitis involving <50% of the colon) should have surveillance every 5 years Intermediate-risk patients (extensive colitis with mildly active endoscopic or histological inflammation, post-inflammatory polyps, or a family history of colorectal cancer in a first-degree relative who was at least 50 years of age) should have surveillance every 3 years High-risk patients (extensive colitis with moderately active endoscopic or histological inflammation, a stricture in the preceding 5 years, dysplasia in the previous 5 years that was not treated surgically, primary sclerosing cholangitis or a family history of colorectal cancer in a first-degree relative aged <50 years) should have annual surveillance. 6.8.2 Pseudomembranous colitis This is acute exudative colitis, almost always due overgrowth of Clostridium difficile. Clostridium difficile infection is usually precipitated by broad-spectrum antibiotics. It is common in elderly or chronically ill people, and the mortality rate may be as high as 20%. Patient-to-patient spread in hospital is common. Diagnosis is by demonstration of the Clostridium difficile toxin in stools in most cases, but rarely by endoscopy (which shows inflamed mucosa with yellow pseudomembranes) when the stool test is negative and there is a strong suspicion. Treatment • • • • • • • • • Discontinue inciting concomitant antibiotics as soon as possible and adopt infection control precautions Oral vancomycin or metronidazole for 10-14 days, depending on the severity of disease (Public Health England 2013 guidelines). Metronidazole is recommended for mild and moderate infections. Vancomycin is reserved for patients with severe infection defined by presence of one of the following severity markers: • WCC >15 109/L; • acutely rising blood creatinine (e.g. >50% increase above baseline); • temperature >38.5°C; or • evidence of severe colitis (abdominal signs, radiology) Patients with an underlying infection requiring prolonged duration of concomitant antibiotics should continue treatment throughout the antibiotic course, plus an additional week after its completion Recent evidence suggests that fidaxomicin, a macrocyclic antimicrobial (bactericidal to C. difficile), which is less disruptive to colonic microflora, should be considered in patients with either high risk of recurrence or recurrent infection Intravenous immunoglobulin (IVIg), which contains C. difficile antitoxin, is recommended as an appropriate adjunct to antibiotics in relapsing and severe C. difficile colitis (by the Department of Health and Public Health England guidance, 2013). Data on this treatment is, however, currently limited to case reports and small case series, which suggests an improvement in about two-thirds of intractable cases There is insufficient evidence to support the use of probiotics, and faecal transplantation is under evaluation Close monitoring of full blood count, CRP, electrolytes and albumin is necessary CT is used to detect toxic megacolon in severe cases, which may need a colectomy Recurrent cases may need a tapering regimen of vancomycin over a period of a few weeks C. difficile can be detected in normal stools but is treated only when it causes diarrhoea. 6.8.3 Familial polyposis coli This is an autosomal dominant condition, caused by mutation in the APC tumour suppressor gene which is located on the long arm of chromosome 5. Estimates of the incidence vary from 1 in 7000– 30 000 of the population in the UK. Multiple adenomata occur throughout the colon; if untreated, malignancy is inevitable, often when patients are aged only 30 or 40 years. Surveillance colonoscopy begins in adolescence and prophylactic colectomy usually follows at around the age of 20 years, in view of the high risk of malignant change. Many patients opt for an ileo-anal pouch. Screening of family members is essential. 6.8.4 Peutz–Jeghers syndrome This is an autosomal dominant condition in which multiple hamartomatous polyps occur throughout the GI tract (particularly in the small bowel). Patients may have mucocutaneous pigmentation and perioral freckles. Lesions may lead to GI haemorrhage and may undergo malignant change (carcinoma is increased 12-fold in patients with this condition). 6.8.5 Hereditary non-polyposis colorectal cancer (HNPCC) This is a dominantly inherited disorder of DNA mismatch repair genes located on chromosomes 2 and 3. Malignancies such as those affecting the colon, breast, ovary and endometrium occur at a young age. Relatives of affected patients require genetic counselling and cancer screening. 6.8.6 Colorectal cancer This is the second most common cause of cancer death in the UK, with an incidence of approximately 44/100 000. A National Bowel Cancer Screening Programme based on faecal occult blood (FOB) testing at 60 years of age, followed by colonoscopy, has been introduced in the UK to good effect. The feasibility of screening using flexible sigmoidoscopy between ages 55 and 64 years is currently being considered. Pathologically, it is an adenocarcinoma usually arising from tubular and villous adenomatous polyps (although in inflammatory bowel disease, malignant change arises directly from the mucosa). The commonest sites are the rectum and sigmoid colon. Risk factors and clinical features of colorectal cancer • Increased incidence • Male sex • Family history • Inflammatory bowel disease, especially ulcerative colitis • Familial polyposis coli • Diet low in fibre, fruit and vegetables • Diet high in fat and red meat • Cholecystectomy (bile salts ‘dumped’ in colon) • Obesity • Genetics Sporadic mutations may occur in the p53, Ras and APC genes. p53 regulates the cell cycle and causes apoptosis • in the event of DNA damage – its loss therefore leads to uncontrolled proliferation of cells • Clinical signs These depend on the site of the lesion; all can cause • weight loss and obstructive symptoms • Right-sided • Iron-deficiency anaemia • Abdominal pain • Abdominal mass • Left-sided • Blood per rectum • Altered bowel habit • Abdominal mass • Rectum • Blood per rectum • Tenesmus • Obstruction • Complications • Local spread to organs and lymph nodes • Metastasis to liver, lung, brain and bone • Obstruction perforation Treatment of colorectal cancer This consists of surgery for cure or symptomatic relief, depending on Duke’s staging (Table 6.3). • Radiotherapy may be used as an adjuvant, particularly to reduce tumour bulk before surgery Adjuvant chemotherapy (eg 5-fluorouracil post-operatively) has been shown to improve • prognosis for patients at Duke’s stages B and C; toxicity is low, so quality of life tends to be good Chemotherapeutic agents such as oxaliplatin plus fluorouracil, plus folinic acid (first-line) and irinotecan (second-line) have been used for advanced colorectal cancer. Biological treatments • such as cetuximab, bevacizumab and panitumumab are not recommended by NICE in the UK as adjunctive therapies in advanced colorectal cancers that have progressed despite first-line chemotherapy Serial monitoring of carcinoembryonic antigen (CEA), a glycoprotein from gastrointestinal • epithelia, may be of use in detecting recurrence. However, surveillance colonoscopies are indicated • Isolated hepatic metastases to a single lobe of liver can be resected Carcinoma complicating inflammatory bowel disease: this is discussed in Section 6.8.1, Crohn’s disease and ulcerative colitis. Table 6.3 Duke’s classification and prognosis of colorectal cancer Stage 5-year survival A – confined to mucosa and submucosa B – extends through muscularis propria C – regional lymph nodes involved D – distant spread 6.8.7 80%+ 60–70% 30–40% 0% Irritable bowel syndrome (IBS) This is a chronic, relapsing, functional gut disorder with no recognisable pathological abnormality. In most cases the diagnosis is based on clinical presentation, although symptoms presenting in older patients require investigation to exclude other pathologies. Faecal calprotectin is a useful test to exclude inflammatory bowel disease and support a diagnosis of irritable bowel syndrome (IBS) in patients with chronic lower gastrointestinal symptoms in whom cancer is not suspected. IBS affects up to 10% of the population, with a ratio of 5:1 female : male. Strict diagnosis is based on the Rome III criteria, requiring recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months, associated with two or more of the following: • Improvement with defecation • Onset associated with a change in frequency of stool • Onset associated with a change in form (appearance) of stool. Full blood count, ESR, CRP, anti-endomysial antibody, TFTs and stool culture are useful screening investigations to exclude common diagnoses, and sigmoidoscopy provides reassurance for patients and clinicians that there is no underlying pathology. • • • • • Bloating, borborygmi, excessive flatus, belching and mucorrhoea are common gastrointestinal symptoms IBS is often associated with variable bowel habit both in stool frequency and consistency, but may also present with ‘diarrhoea-dominant’ or ‘constipation-dominant’ symptoms Patients with IBS often complain of other ‘functional’ symptoms and have a higher prevalence of fibromyalgia, non-cardiac chest pain, tension headache, sterile cystitis, dyspareunia, back pain, myalgic encephalopathy, anxiety and depression There is a clear association with a history of childhood abuse In about a quarter of cases IBS is preceded by gastrointestinal infection, raising the possibility of damage to the neuroenteric innervation in some cases. Treatment of irritable bowel syndrome Treatment is usually symptomatic and until recently has been limited to antispasmodics, increased dietary fibre, laxatives, constipating agents, antidepressants, hypnotherapy and psychotherapy. The last therapies are particularly useful for patients whose symptoms occur on a background of significant psychological morbidity. Extensive research and clinical trials to improve patient phenotyping and development of novel treatment targets for IBS holds promise for more tailored treatment options in the future. One such treatment, prucalopride (a 5HT4 agonist), has NICE approval for treatment of ‘constipation-dominant’ IBS (IBS-C) in females who have persistent symptoms despite having tried at least two laxatives from different classes, at the highest tolerated recommended doses for at least 6 months. Another novel treatment licensed in moderate-to-severe IBS-C, linaclotide (guanylyl cyclase C receptor agonist), has the added advantage of improving visceral pain in addition to colonic transit. 6.9 GASTROINTESTINAL INFECTIONS AIDS and the gut is covered in Chapter 8, Genitourinary Medicine and AIDS. 6.9.1 Gastroenteritis Most gastrointestinal infections in the UK are viral or self-limiting bacterial infections such as Staphylococcus aureus or Campylobacter. Most patients require no treatment, but antidiarrhoeals (such as loperamide) and oral rehydration therapy (ORT) may be required in patients who are at risk of dehydration. ORT utilises the capacity of the small bowel to absorb chloride, sodium and water via a glucose-dependent active transport channel that is not disrupted by infections. More intensive therapy is confined to those systemically unwell or immuno-suppressed. The following are some of the more important gastrointestinal infections. (See also Chapter 11, Infectious Diseases and Tropical Medicine.) Amoebiasis • Infection is due to Entamoeba histolytica with faecal–oral spread The clinical spectrum ranges from mild diarrhoea to dysentery with profuse bloody stool; a • chronic illness with irritable bowel-type symptoms may also occur. Colonic or hepatic abscesses occur, the latter commonly in the setting of a severe amoebic colitis • Treatment is with metronidazole. Campylobacter This is due to a Gram-negative bacillus; spread is faecal–oral. • Gram-negative rods Clinically, patients are often systemically unwell with headache and malaise prior to the onset of • diarrhoeal illness. Abdominal pain may be severe, mimicking an acute abdomen • Erythromycin may be indicated if symptoms are prolonged. Cholera Infection is due to Vibrio cholerae (Gram-negative rods) which colonise the small bowel; • spread is faecal–oral. A high infecting dose is needed as the bacteria are susceptible to gastric acid A severe toxin-mediated diarrhoea occurs with ‘rice-water’ stool which may exceed 20 litres • per day. Dehydration is the main cause of death, especially in young or elderly, and mortality is high without rehydration treatment • Tetracycline may reduce transmission Giardiasis Infection is due to Giardia lamblia (a flagellate protozoan) which colonises the duodenum and jejunum; spread is faecal–oral Bloating and diarrhoea (not bloody) occur and may be chronic. Malabsorption may occur with • small-intestinal colonisation. Asymptomatic carriage is common and duodenal biopsy may be necessary to make the diagnosis in patients with chronic diarrhoea or malabsorption symptoms • Treatment is with metronidazole • Salmonella • • • • • A Gram-negative bacillus, Salmonella Typhimurium, with multiple serotypes divided into two main groups: those causing typhoid and paratyphoid (enteric fever), and those causing gastroenteritis (food poisoning). Spread is faecal–oral Diarrhoea (may be bloody) occurs, with or without vomiting and abdominal pain Rose spots tend to appear on the chest and abdomen about 2 weeks after the onset of symptoms Diagnosis is made by blood culture Treatment is supportive, but occasionally ciprofloxacin or trimethoprim may be required for chronic symptoms or severe illness in the very young or elderly. Shigella Gram-negative rods. Spread is faecal–oral with a very low infecting dose of organisms needed owing to its high virulence The clinical spectrum ranges from diarrhoeal illness to severe dysentery, depending on the • infecting type: S. sonnei, S. flexneri, S. boydi, S. dysenteriae • Diarrhoea (may be bloody), vomiting, abdominal pain • Treat if severe with ampicillin or tetracycline, although there is widespread resistance • 6.9.2 Gastrointestinal tuberculosis This is common in developing countries, and causes ileocaecal TB (mimicking Crohn’s disease) or occasionally spontaneous TB peritonitis. There has been a recent increase in abdominal TB, particularly in patients with AIDS. The infection may occur secondary to pulmonary TB as a result of swallowing infected sputum or by haematogenous spread. Clinical features are often non-specific, such as malaise, fever and weight loss, as well as diarrhoea and abdominal pain Ultrasound, barium studies or CT may suggest the diagnosis, but biopsy, either by laparoscopy or • endoscopy, is confirmative • Treatment is with conventional anti-tuberculous therapy • 6.10. HEPATOLOGY 6.10.1 Jaundice Jaundice is one of the most common symptoms of liver disease, caused by the accumulation of bilirubin in the tissues. Bilirubin is formed as the end product of catabolism of haem-containing compounds and is clinically detectable at a level of >35 umol/l. The formation and excretion of bilirubin is shown in Figure 6.4. The most common causes of jaundice in the UK are alcoholic liver disease, gallstones and tumours of the liver and pancreas. Hyperbilirubinaemia may occur because of excess production or decreased elimination of bilirubin (Table 6.5). Jaundice can thus be broadly divided into three categories depending on the site of the pathology. Causes of jaundice The following classification is used (Table 6.4): Pre-hepatic: excess production of bilirubin or failure of uptake into the liver. Bilirubin is unconjugated and insoluble, so it does not appear in the urine–acholuric jaundice Hepatic: defect is at the level of hepatocyte. There is diminished hepatocyte function, and so • both conjugated and unconjugated bilirubin appear in the urine Post-hepatic: there is impaired excretion of bile from liver into the gut. Conjugated bilirubin is therefore reabsorbed, which increases serum and urine levels and produces dark urine. The • stools become pale due to lack of stercobilinogen; urobilinogen (produced in the gut – see Figure 6.4) becomes undetectable in urine. • Table 6.4 Causes of jaundice Pre-hepatic Haemolysis causing excess haem production Congenital hyperbilirubinaemia (eg Gilbert syndrome, Crigler–Najjar syndrome (see Table 6.5) Hepatic Alcoholic hepatitis Viral infection (eg hepatitis A, B, Epstein–Barr virus) Drugs (eg phenothiazines, augmentin and other antibiotics) Wilson’s disease Rotor and Dubin–Johnson syndromes (see Table 6.5) Cirrhosis Multiple hepatic metastases Hepatic congestion in cardiac failure Post-hepatic Gallstones Carcinoma of pancreas or bile ducts Lymph nodes at porta hepatis (eg metastatic, lymphomatous) Primary biliary cirrhosis – small-bile-duct obliteration Sclerosing cholangitis Structural abnormality of the biliary tree – post-surgery, congenital (eg biliary atresia) Investigation of jaundice Figure 6.5 shows a typical systematic approach. Figure 6.4 Enterohepatic circulation of bile. Figure 6.5 Investigation of jaundice Blood tests Liver function tests (see Table 6.6) may indicate if jaundice is obstructive (elevated alkaline phosphatase from cells lining canaliculi) or hepatocellular (elevated transaminases). Patients with chronic liver disease may have normal enzyme levels but poor synthetic function (low • albumin, prolonged prothrombin time) – will indicate a hepatic aetiology. Full blood count, reticulocyte count, haptoglobins, Coombs’ test and blood film should be performed if haemolysis is suspected Viral serology (hepatitis A, B and C), autoantibody titres (antimitochondrial M2 for primary biliary cirrhosis and anti-smooth muscle for chronic autoimmune hepatitis), α1-antitrypsin, α• fetoprotein (AFP), ferritin and copper studies are essential when investigating unexplained jaundice or chronic liver disease. Imaging and biopsy • • • • • • Liver ultrasound: is the single most useful radiological test and will identify obstruction, metastases, cirrhosis and hepatoma CT scanning: is frequently used to complement ultrasound images, to define lesions more clearly and to diagnose lesions not seen on ultrasound MRCP: is non-invasive and is a highly accurate technique which has become the diagnostic test of choice in evaluating patients with biliary obstruction Endoscopic ultrasound (EUS): is useful when non-invasive methods such as ultrasound and MRCP fail to yield a diagnosis for biliary duct dilatation, providing complete and detailed imaging of the biliary system, with a much lower complication risk than ERCP (0.03%) ERCP: is no longer used as a diagnostic test in obstructive jaundice due to the procedural risk of complications (>5%). It should always be interventional to stent obstructing tumours or remove obstructing gallstones identified on the above imaging modalities Liver biopsy: may be helpful in non-obstructive jaundice, but is contraindicated in the presence of uncorrected coagulation disorders, and is technically difficult if ascites is present. Table 6.5 Classification of congenital hyperbilirubinaemia Syndrome Genetics Defect Clinical features Autosomal Defect in Increased unconjugated bilirubin Treatment Gilbert dominant conjugation Asymptomatic jaundice, Nil as benign condition increases with fasting Crigler– Najjar Type 1 – autosomal recessive Type 2 – autosomal dominant Both due to defective conjugation Dubin– Johnson Autosomal recessive Defect in hepatic excretion Jaundice with right upper quadrant pain and Nil as benign condition malaise Rotor Autosomal recessive Defect in uptake and storage of bilirubin Increased conjugated bilirubin Neonatal kernicterus and death Jaundice as neonate/ child; survive to adulthood None; fatal Phenobarbital to decrease jaundice Nil as benign condition Table 6.6 Liver function tests in jaundice ↑ Moderately raised; ↑↑ raised. 6.10.2 Gallstone disease Gallstones are one of the commonest causes of jaundice, usually presenting with right hypochondrial or epigastric pain and cholestatic liver function tests. Approximately 1 litre of bile is secreted by the hepatocytes each day. Half of this drains directly into the duodenum, whilst the remainder is stored and concentrated in the gall bladder by removal of sodium, chloride, bicarbonate and water. Cholecystokinin (CCK) then stimulates its release. Stones are found in 10–20% of the population (with a female preponderance), but are asymptomatic in the majority 70–90% of gallstones are a mixture of cholesterol and bile pigment and 10% are pure • cholesterol. Pure pigment stones are rare except with chronic haemolysis (eg sickle cell disease, spherocytosis). • Risk factors for and clinical presentation of gallstones • Risk factors for stone formation • Female sex • • Increasing age • Drugs (eg oral contraceptive pill, clofibrate) • Crohn’s disease (terminal ileum) • Short-bowel syndrome • Haemolysis (pigment stones) Clinical presentation • Acute/chronic cholecystitis • Biliary colic • Cholestatic jaundice if duct obstruction • Pancreatitis • Cholangitis • Gallstone ileus NB: Stones may form in the common bile duct even after cholecystectomy. Diagnosis in most cases may be established by ultrasound. MRCP has replaced ERCP as a useful, non-invasive investigation. EUS, where available, is the most sensitive test for • diagnosing stones and is useful when noninvasive investigations fail to demonstrate a cause for biliary dilatation. ERCP is reserved to deal with stones that have been confirmed by other imaging investigations Definitive treatment is by cholecystectomy. ERCP with sphincterotomy and balloon clearance of the common bile duct is indicated for intraductal stones. Medical treatment with ursodeoxycholic • acid can be used to dissolve cholesterol stones; however, this is extremely slow and should be reserved only for patients who are unfit for other treatment. 6.10.3 Ascites Ascites is defined as the accumulation of free fluid within the peritoneal cavity. It can be subdivided into transudate or exudate (Table 6.7) depending on whether the protein content is less or greater than 30 g/l, respectively. The most common causes in the UK are cirrhosis and malignant disease. The treatment of ascites depends on the aetiology. Transudates respond to fluid restriction, low sodium intake and diuretic therapy, to promote sodium and water excretion via the kidneys. Aldosterone antagonists (spironolactone) are firstline diuretics (BSG and EASL guidelines) with a starting dose of 100 mg, increasing stepwise every 7 days if there is no response up to a maximum of 400 mg/day. In failure of aldosterone antagonists (failure to lose 2 kg/week or development of hyperkalaemia), furosemide should be added 40 mg/day, increasing stepwise to a maximum of 160 mg/day. Patients should undergo • frequent clinical and biochemical monitoring. Once ascites has largely resolved, doses should be reduced to the minimum required or discontinued. Paracentesis may be used for tense ascites or ascites that is not responding to diuretics. However, paracentesis may result in a further shift of fluid from the intravascular space into the peritoneal cavity with the risk of circulatory collapse. This can be reduced by supporting the circulation using intravenous albumin. The drain should be removed at the earliest opportunity (typically after 6 hours) because of the risk of introducing infection, which can in turn lead to decompensation of liver disease • Exudates can be safely paracentesed without protein replacement. Table 6.7 Causes of ascites Transudate Portal hypertension Nephrotic syndrome Malnutrition Cardiac failure Budd–Chiari syndrome Myxoedema Exudate Hepatic or peritoneal malignancy Intra-abdominal TB Pancreatitis Hepatorenal syndrome (HRS) • • Acute kidney injury can complicate chronic liver disease, but it can also occur with fulminant hepatic failure: Type 1 HRS occurs as a rapidly progressive renal impairment, with a very high mortality • rate, all patients dying within weeks without treatment In Type 2 HRS renal impairment is more stable and some hepatic reserve is preserved. • Mortality is again high, but some patients survive over 6 months The benefits of dialysis in hepatorenal syndrome are limited and it is not recommended in patients with decompensated cirrhosis who are not candidates for liver transplantation (Acute Dialysis Quality Initiative [ADQI] guidelines–2012). Spontaneous bacterial peritonitis Patients with cirrhosis and ascites are at risk of spontaneous bacterial peritonitis (SBP), which may present with local symptoms or features of peritonitis, signs of sepsis, deterioration in liver function, hepatic encephalopathy, renal failure and gastrointestinal bleeding. An ascitic fluid neutrophil count of ≥250 / mm3 is diagnostic on paracentesis, and appropriate empirical antibiotics with Gramnegative cover should be started once diagnosis has been confirmed. Patients who present with SBP should be treated with intravenous albumin because this has been shown to decrease the incidence of hepatorenal syndrome and improve survival (European Association for the Study of the Liver [EASL] clinical practice guidelines – 2010). 6.10.4 Viral hepatitis The six major hepatitis viruses are described below, but further types are already postulated. Hepatitis B and C in particular are major causes of morbidity and mortality worldwide, although recent advances in treatment with interferon and other antivirals have improved the outcome in certain groups. Hepatitis A Spread: faecal–oral Virus: RNA Clinical: anorexia, jaundice, nausea, joint pains, fever Treatment: supportive Chronicity: no chronic state Vaccine: yes Hepatitis B Spread: blood-borne (eg sexual, vertical, congenital transmission) Virus: DNA Clinical: acute fever, arteritis, glomerulonephritis, arthropathy Treatment: supportive; EASL guidance recommends that patients should be considered for treatment when they have HBV DNA levels above 2000 IU/ ml, serum ALT levels above the upper limit of normal and severity of liver disease assessed by liver biopsy showing moderate-to-severe active necroinflammation. Treatment options include interferon and the antiviral agents lamivudine, adefovir, tenofovir, entecavir and telbivudine (with an aim to acheive seroconversion to anti-HBe and achieve reduction in viral replication [HBV DNA levels] and reduce histological activity of chronic hepatitis) Chronicity: 5% progress to chronic carriage (risk of cirrhosis and hepatocellular carcinoma) Vaccine: yes Hepatitis C Spread: blood-borne, sexual Virus: RNA Clinical: acute hepatitis – less severe than A or B, fulminant failure rate Treatment: pegylated interferon-alpha (interferon bound to polyethylene glycol) for chronic HCV. This may be more effective when used in combination with ribavirin Chronicity: 60–80% develop chronic hepatitis, and 20% of these progress to cirrhosis (of whom a third will develop hepatocellular carcinoma). IV- drug-related hepatitis C represents a major public health problem in the UK Vaccine: no Hepatitis D (delta agent) Spread: blood-borne (dependent on concurrent hepatitis B infection for replication) Virus: incomplete Clinical: exacerbates established hepatitis B infection and increases risk of hepatic failure and cirrhosis Treatment: interferon of limited benefit Chronicity: increases incidence of cirrhosis in chronic HBV Vaccine: no Hepatitis E Spread: faecal–oral Virus: RNA Clinical: acute self-limiting illness, but there is a 25% mortality (fetal and maternal) in pregnancy, which increases in later stages of gestation Treatment: supportive Chronicity: no chronic state Vaccine: no Hepatitis G Spread: blood-borne Virus: RNA Clinical: doubtful relevance; 20% of patients with chronic HCV are infected with hepatitis G Treatment: viraemia may decline with interferon Chronicity: unknown – may cause cirrhosis and hepatocellular carcinoma Vaccine: no Interferon in viral hepatitis Virological response to treatment is defined as an HBV DNA concentration of less than 2000 IU/ml. It is usually evaluated at 6 months and at the end of therapy, as well as at 6 and 12 months after the end of therapy. Interferon is predominantly of benefit in patients suffering from chronic hepatitis B and C. In hepatitis B, there is a response in 40% of chronic carriers. The response is poorer in Asian patients. The response is likely to be very poor if the patient is also infected with HIV, and thus treatment is not usually indicated in this group. In hepatitis C, there is a response in 50% of chronic carriers, but 50% of these will relapse despite treatment. Hepatitis B serology Antigens/antibodies related to viral surface (s), envelope (e) and core (c) are useful for determining the stages, infectivity and chronicity of hepatitis B infection: • • • • • • • HBsAg: present in acute infection; if present longer than 6 months, then 25% develop chronic hepatitis HBeAg: present in acute or chronic infection; signifies high infectivity HBcAg: present in acute or chronic infection; found only in liver tissue; present for life Anti-HBs: signifies immunity after vaccination or acute infection Anti-HBe: signifies declining infectivity and resolving infection Anti-HBe IgM: signifies recent acute infection; lasts less than 6 months Anti-HBc IgG: a lifelong marker of past acute or chronic infection; does not signify immunity or previous vaccination 6.10.5 Drug-induced hepatitis Many drugs can cause hepatitis. Toxicity may be due to overdose (eg paracetamol), idiosyncratic (eg flucloxacillin) or may be related to dosage or duration of therapy (eg azathioprine). Three patterns of damage can occur: • • • Cholestasis: some drugs produce a functional obstruction to bile flow by causing bile duct inflammation and interfering with excretory transport mechanisms. The commonest examples are flucloxacillin, erythromycin, chlorpromazine, oral contraceptives and anabolic steroids True hepatitis: some drugs produce direct hepatocellular damage which may be trivial or result in fulminant liver failure. Several mechanisms are responsible. Common examples include statins, anti-tuberculous drugs, immunosuppressants, ketoconazole and halothane Hepatic necrosis: if the ability of the liver to detoxify metabolites is overwhelmed, glutathione levels fall and toxic metabolites accumulate, causing liver necrosis. This is the pattern of damage with carbon tetrachloride ingestion and paracetamol overdosage. Other causes of acute hepatitis include: • alcohol • other viruses (eg Epstein–Barr, yellow fever, CMV, rubella, herpes simplex) • other infections (eg malaria, toxoplasmosis, leptospirosis, brucellosis). 6.10.6 Autoimmune hepatitis This condition occurs predominantly in female patients. Other autoimmune disease is often present and patients are usually antinuclear antibody-positive. Other antibodies associated with autoimmune hepatitis include anti-smooth muscle and anti-liver kidney microsomal-1 antibody, and anti-double stranded DNA antibody is present in 15% of cases. Autoimmune hepatitis responds to steroids and azathioprine, but the majority progress to cirrhosis, although 90% are alive at 5 years and may be candidates for transplantation. 6.10.7 Cirrhosis Cirrhosis is characterised by the irreversible destruction and fibrosis of normal liver architecture with some regeneration into nodules. There are four stages of pathological change: • • • • liver cell necrosis inflammatory infiltrate fibrosis nodular regeneration. Regeneration may be macronodular (eg alcohol- or drug-induced), micronodular (eg viral hepatitis) or mixed, but a more useful categorisation is according to the aetiological agent. Causes of cirrhosis • • • • • • • • • Alcohol (most common in the UK, approximately 30% of all cases) Haemochromatosis Hepatitis B or C (most common worldwide) α1-antitrypsin deficiency Cryptogenic Primary biliary cirrhosis Wilson’s disease Non-alcoholic steatohepatitis (NASH) Autoimmune hepatitis Evidence of chronic liver disease may or may not be present. Clinical features of cirrhosis Clinical features are related to hepatic insufficiency: • Confusion/encephalopathy: due to failure of liver to metabolise ammonium salts Haemorrhage: bruising/bleeding/petechiae secondary to deficiency in factors II, VII, IX and X, • and thrombocytopenia • Oedema: secondary to hypoalbuminaemia • Ascites: due to portal hypertension, hypoalbuminaemia and secondary hyperaldosteronism • Jaundice: failure to metabolise and/or excrete bilirubin Other clinical features include: palmar erythema, spider naevi, Dupuytren’s contracture, caput • medusae and splenomegaly (due to portal hypertension) • Gastrointestinal haemorrhage secondary to varices (oesophageal, gastric or rectal) • Hepatorenal syndrome Diagnosis of cirrhosis Cirrhosis may be suspected on ultrasonography but diagnosis can be confirmed histologically via ultrasound-guided liver biopsy, which may also help identify the aetiology. An ultrasound-guided approach to biopsy is mandatory because the liver is often very small. Rarely, a transjugular biopsy may be required, particularly if clotting is markedly deranged. The disadvantages of liver biopsy include its invasiveness and post-procedural risks such as pain and bleeding. Recently, transient elastography (Fibroscan) has been developed to determine the degree of liver fibrosis via a noninvasive technique. This involves passage of sound waves through the liver via a transducer at the end of an ultrasound probe; the velocity of these sound waves is then converted into a measure of liver stiffness. In addition to non-invasiveness, advantages include instantly available results. Indications for liver biopsy (adapted from AASLD position paper Liver Biopsy – Hepatology, 2009) • • • • • • Guide management plans based on histological analysis (eg. viral hepatitis, autoimmune hepatitis) Persistently abnormal liver enzymes of unknown cause Prognosticate and stage known parenchymal liver disease Confirm a diagnosis of non-alcoholic fatty liver disease Focal liver lesions identified on imaging studies Multiple parenchymal liver diseases, eg overlap of PBC and autoimmune hepatitis or steatosis with viral hepatitis Treatment of cirrhosis Treatment is aimed at the removal of causal factors such as alcohol. Specific treatments include interferon for viral hepatitis and ursodeoxycholic acid for primary biliary cirrhosis. Transplantation is the best hope but many patients are not suitable. Contraindications for liver transplantation include: • Poor cardiac reserve • Co-morbidity such as HIV infection or severe respiratory disease • Failure to abstain from alcohol. There is no definitive cut-off regarding age, but patients over 70 years are less likely to be suitable. Conditions which may be amenable to hepatic transplantation • Fulminant hepatic failure (eg due to hepatitis C or paracetamol toxicity) • Primary biliary cirrhosis • Wilson’s disease Hepatitis B – although there is frequent recurrence after transplant; this can be reduced with pre• transplant treatment with interferon • Cholangiocarcinoma – if unresectable at presentation • Alcohol – following psychological review and if abstained for more than 6 months • Haemochromatosis • Hepatocellular carcinoma – if not multifocal, if <5 cm and no evidence of vascular invasion 6.10.8 Portal hypertension and varices Portal hypertension occurs as a result of increased resistance to portal venous flow. Pressure in the portal vein rises and is said to be pathological when >12 mmHg, although pressures of up to 50 mmHg may occur. The spleen enlarges and anastomoses may open between the portal and systemic circulation. Some of the collaterals, which most commonly occur at the oesophagogastric junction, umbilicus and rectum, may become very large, with a risk of bleeding. A variety of conditions may cause portal hypertension; in the UK, the single most common is cirrhosis secondary to alcohol. Causes of portal hypertension • Cirrhosis due to any cause • Portal vein thrombosis (congenital malformation, pancreatitis, tumour) Budd–Chiari syndrome (thrombosis or obstruction of hepatic vein due to tumour, haematological • disease or the oral contraceptive pill) • Intrahepatic tumours such as cholangiocarcinoma or hepatocellular carcinoma • Constrictive pericarditis • Right heart failure • Splenic vein thrombosis (segmental portal hypertension) Variceal haemorrhage Thirty per cent of patients with varices will bleed at some point, with a mortality of 50% for that episode. The majority of survivors will rebleed, with a mortality of 30%. Bleeding is often catastrophic as many patients also have coagulopathy as a result of their underlying liver disease. Primary prevention of haemorrhage All patients with cirrhosis of the liver should have upper GI endoscopy to determine the presence or absence of varices. If there are none, or only very small varices, no treatment is required except regular endoscopic review every 2–3 years. Larger varices in patients with no history of variceal haemorrhage should be treated with prophylactic, non-selective β blockers (such as propranolol or carvedilol), alone or in combination with a nitrate (nitrates given alone are of no benefit). These reduce portal pressure and thus the risk of haemorrhage. Patients intolerant of β blockers and who are at high risk of bleeding may be considered for endoscopic variceal ligation. Treatment of variceal haemorrhage (see Figure 6.3) After resuscitation and correction of coagulopathy and thrombocytopenia, vasoactive drugs, such as terlipressin (Glypressin), should be concomitantly prescribed with antibiotics at presentation of suspected variceal bleeding. Confirmation of diagnosis and treatment of choice is early gastroscopy with band ligation of oesophageal varices (now shown to be superior to injection sclerotherapy). Gastric varices should be treated endoscopically with injection sclerotherapy using N-butyl-2cyanoacrylate. Temporary balloon tamponade (Sengstaken–Blakemore tube) may be useful if endoscopy is not immediately available or bleeding cannot be stopped endoscopically. Bleeding that does not respond to these measures may be an indication for emergency transjugular intrahepatic portosystemic shunting (TIPSS). Secondary prevention of haemorrhage Patients should undergo repeated band ligation until varices are eradicated. Beta blockers should be given as this reduces the risk of rebleeding by up to 40%. Recurrent haemorrhage may be an indication for TIPSS. Transjugular intrahepatic portosystemic shunting (TIPSS) This involves placement of a shunt under radiological screening which decompresses the portal venous system. Anatomically the shunt connects the portal vein (high pressure) to the hepatic vein (low pressure). As it is less invasive than surgery, it may be a useful rescue procedure for patients with recurrent or resistant haemorrhage who are not fit for surgery. The major problems are that shunting may precipitate hepatic encephalopathy (this occurs in up to 24%, but seems more responsive to treatment than encephalopathy from other causes), and shunt blockage. In the latter case, a second shunt may be ‘piggy-backed’ across the first. TIPSS may be particularly helpful as a palliative procedure in patients with recurrent haemorrhage due to malignancy. 6.10.9 Hepatic encephalopathy Hepatic encephalopathy is a neuropsychiatric syndrome which may complicate acute or chronic liver disease from any cause. Symptoms include confusion, falling level of consciousness, vomiting, fits and hyperventilation. Acute kidney injury may often supervene – the chance of recovery from hepatorenal failure is extremely poor. The underlying mechanisms are complex, but the absorption of toxins, such as ammonia, from bacterial breakdown of proteins in the gut is thought to play a major part. Portosystemic shunting of blood occurs – toxins thus bypass the liver and cross the blood–brain barrier. The most common causes of acute hepatic encephalopathy are fulminant viral hepatitis and paracetamol toxicity, which are potentially fully reversible. Indicators of poor prognosis are: • worsening acidosis • rising prothrombin time • falling Glasgow Coma Scale score. These patients should be referred to a specialist centre as they may need transplantation. Chronic hepatic encephalopathy may supervene in chronic liver disease of any type. It is often precipitated by: • • • • • alcohol drugs GI haemorrhage infections constipation. It is characterised by a flapping tremor, decreased consciousness level and constructional apraxia. Treatment of hepatic encephalopathy • • • • • • • Screen for and treat sepsis aggressively – if ascites is present, consider bacterial peritonitis and perform a diagnostic ascitic tap. There should be a low threshold for prescribing antibiotics Strict fluid and electrolyte balance High protein diet Laxatives (lactulose) to clear the gut and thus reduce toxin absorption; neomycin is now rarely used Rifaxamin, a semi-synthetic antibiotic which decreases intestinal production and absorption of ammonia, has shown promise in clinical trials in maintaining remission in patients with hepatic encephalopathy. This drug is currently being appraised by NICE Remove or treat precipitants Mortality is high, especially if renal failure supervenes, when the mortality exceeds 50% 6.10.10 Primary biliary cirrhosis Primary biliary cirrhosis accounts for approximately 5% of deaths due to cirrhosis. The cause is unknown although environmental and genetic factors and autoimmune aetiology are suggested in the literature, especially given the strong association with other autoimmune disease such as rheumatoid arthritis, Sjögren syndrome and CREST syndrome. Histologically, progressive inflammation and destruction of small intrahepatic ducts leads to eventual cirrhosis. Ninety per cent of patients are female, often in middle age. There are four stages of primary biliary cirrhosis: 1. Destruction of interlobular ducts 2. Small-duct proliferation 3. Fibrosis 4. Cirrhosis. Primary biliary cirrhosis • • Clinical features • Cholestatic jaundice • Xanthelasmata due to hypercholesterolaemia • Skin pigmentation • Clubbing • Hepatosplenomegaly • Portal hypertension varices • Osteoporosis and osteomalacia Diagnosis • • • • Antimitochondrial (M2) antibody present in 95% Predominantly raised alkaline phosphatase – often raised in advance of symptoms/signs Raised IgM Liver biopsy showing the features listed above Treatment is symptomatic; cholestyramine relieves pruritus. Ursodeoxycholic acid is widely used, but it is doubtful whether this agent either improves the prognosis or delays time to liver transplantation. Rising bilirubin levels are an indication that the disease is approaching end-stage, and as liver transplantation remains the only hope of cure, patients should be assessed for this later treatment at an appropriate stage of their disease process. 6.10.11 Other causes of chronic liver disease Haemochromatosis: this is an autosomal recessive disorder of iron metabolism leading to deposition in the liver, pancreas, pituitary and myocardium. (See Chapter 13, Metabolic Diseases.) Wilson’s disease: this is an autosomal recessive disorder of copper metabolism causing deposition in the liver, basal ganglia and cornea (Kayser–Fleischer ring). (See Chapter 13, Metabolic Diseases.) Non-alcoholic fatty liver disease (NAFLD): NAFLD is the most common cause of liver disease in the West and accounts for a growing proportion of liver transplant patients. Diagnosis requires demonstration of hepatic steatosis (imaging or histology) without significant alcohol consumption history. Histologically, NAFLD is divided into non-alcoholic fatty liver (NAFL), which is common (33% of UK population), and non-alcoholic steatohepatitis, inflammation with hepatocyte injury (ballooning) with or without fibrosis (NASH), which affects 2-5% of UK population. Conditions associated with NAFLD: • • • • obesity type 2 diabetes mellitus dysplipidaemia metabolic syndrome. Other causes of parenchymal liver disease should be excluded. Liver biopsy should be considered in patients with higher risk (eg metabolic syndrome) for steatohepatitis and advanced fibrosis, and those in whom coexisting chronic liver diseases cannot be excluded without biopsy. Patients often have no specific symptoms. Treatment should focus on managing lifestyle factors, cardiovascular and metabolic risk factors. In particular, there is evidence that exercise and loss of 3–5% of body weight can regress steatosis. The British Society of Gastroenterology advises that diabetic control must be optimised, including metformin and GLP-1 analogues, and consideration of thiazolidinediones (pioglitazone) Orlistat and Vitamin E. Patients with NASH cirrhosis will require surveillance for hepatocellular carcinoma, oesophageal varices and features of decompensation (ascites, jaundice, encephalopathy, malnutrition). Bariatric surgery is thought to be beneficial in NASH, with reports of improved liver histology and glycaemic control. 6.10.12 Parasitic infections of the liver Hydatid disease This is caused by Echinococcus granulosus (a dog tapeworm), and is most common in areas of sheep and cattle farming. Ingestion results from eating contaminated vegetables or as a result of poor hand hygiene. The parasitic embryos hatch in the small intestine and enter the bloodstream via the portal venous circulation to the liver, but there may also be spread to lung or brain. Many cases are asymptomatic, but right upper quadrant pain is the commonest symptom. Jaundice occurs if there is duct obstruction, and peritonitis will result from cyst rupture Diagnosis is confirmed using a haemagglutination test, but eosinophilia or the presence of cystic • lesions on liver ultrasound in an at-risk individual is strongly suggestive of the disease Active infection is treated with albendazole followed by surgical resection of the intact cyst. • Chronic calcified cysts can be left untreated. • Schistosomiasis This affects about 250 million people worldwide. It is caused by Schistosoma mansoni (Africa, South America) or Schistosoma japonicum (Asia). Infection occurs when the parasite penetrates the skin during swimming or bathing in infected water contaminated by the intermediate host – the freshwater snail. The parasite migrates to the liver via the portal venous system where it matures, migrates back along the portal (and mesenteric) veins and produces numerous eggs which penetrate the gut wall and are excreted to continue the cycle. A chronic granulomatous reaction occurs in the liver leading to periportal fibrosis and cirrhosis. Early symptoms are related to the site of entry of the organism (swimmer’s itch) and systemic effects, including malaise, fever, myalgia, nausea and vomiting Diagnosis confirmed by detecting ova in stool or liver biopsy. Liver function tests show raised • alkaline phosphatase, and there is an eosinophilia • Treatment is with praziquantel. • 6.10.13 Hepatic abscesses Pyogenic abscesses most commonly occur following intra-abdominal sepsis, but they can occur spontaneously. The most common organism isolated is E. coli but Enterococcus, Proteus, Staphylococcus aureus and anaerobes are recognised. Patients present with swinging pyrexia, weight loss, right upper quadrant pain and anorexia. Septic shock or jaundice may develop Diagnosis is confirmed by liver ultrasound, which is used to guide aspiration or insertion of a • drain Broad-spectrum antibiotics are given until sensitivities are available; occasionally surgical • resection is required. • Amoebic abscesses are caused by Entamoeba histolytica which spreads from the gut (where it can cause an acute diarrhoeal illness) via the portal system to the liver. Single or multiple abscesses may be found on ultrasound and treatment is with metronidazole. 6.10.14 Hepatobiliary tumours There are a number of types of primary hepatic malignancy, all of which are rare. Secondary tumours, however, are common, typically metastasising from the stomach, colon, breast and lung. Treatment of metastatic tumours is usually not indicated as the disease process is far advanced, although chemotherapy may slow progression in selected patients. Hepatocellular carcinoma This is rare in the UK (1–2/100 000 population), but the incidence is increased 20–30 times in Africa, Asia and Japan. Incidence is increased by: • • • • Hepatitis B (commonest cause worldwide) and hepatitis C virus Cirrhosis from any cause, particularly hepatitis B and C and haemochromatosis Aflatoxin – a carcinogen from the mould Aspergillus flavus which may contaminate food Long-term oral contraceptive use. Raised serum α-fetoprotein (AFP) suggests the diagnosis and in association with ultrasound, has been suggested as an appropriate 6 monthly screening for patients with cirrhosis (EASL guidelines, 2012). The treatment and prognosis are outlined in Table 6.8. Table 6.8 Treatment and prognosis of hepatocellular carcinoma Treatment Prognosis Resection Only 5–15% are suitable, with 20% operative mortality; 5-year survival <30% Transplant Very few patients are suitable – they should have single tumours smaller than 5 cm with no vascular or metastatic spread; 5-year survival 90% Chemotherapy/ethanol injection into tumour/embolisation Palliative with little survival benefit Cholangiocarcinoma This is an uncommon adenocarcinoma arising from the biliary epithelium. It usually presents with obstructive jaundice. Predisposing factors: • Sclerosing cholangitis • Choledochal cyst or other biliary tract abnormality • Liver fluke infection Caroli’s disease (dilatation of the intrahepatic bile ducts predisposing to infection and stone • formation). The treatment and prognosis of cholangiocarcinoma are outlined in Table 6.9. Palliative stenting relieves jaundice and improves quality of life. Carcinoma of the gallbladder This adenocarcinoma occurs in the elderly, but is uncommon. It has usually invaded locally or metastasised by the time of diagnosis. Benign hepatic adenoma The incidence of this is increased in patients who have been taking oral contraceptives for longer than 5 years, and also with the use of anabolic steroids. It is usually asymptomatic but may, rarely, cause intraperitoneal bleeding or right upper quadrant pain. Hepatic haemangioma This is common, and is often an incidental finding on ultrasound. It is benign, but may occasionally rupture. Table 6.9 Treatment and prognosis of cholangiocarcinoma Treatment Prognosis No treatment Average survival 2 months Fewer than 20% of patients are suitable; average survival approximately 3 years Very few patients are suitable, but this gives the best prognosis Resection Transplant 6.11. ACUTE ABDOMEN An acute abdomen is one of the more frequent presentations to the Accident and Emergency department. Commoner causes are given in Table 6.10. Table 6.10 Acute abdomen: causes Bowel Acute appendicitis Perforated viscus Inflammatory bowel disease Diverticular disease Bowel obstruction Mesenteric ischaemia Incarcerated inguinal hernia Incarcerated femoral hernia Volvulus Intussusception Pelvic organs Torsion of ovaries Pelvic inflammatory disease Endometriosis Pancreas Acute pancreatitis Acute on chronic pancreatitis Gallbladder/ biliary system Cholecystitis Cholangitis Peritoneum Peritonitis Kidneys Renal calculi Spleen Splenic infarcts 6.11.1 • • • • • • Investigations of acute abdomen Bloods: full blood count, urea and electrolytes, liver function tests, CRP, amylase, arterial blood gases, calcium Chest X-ray Abdominal X-ray ECG CT scan of abdomen Laparotomy. Chapter 7 Genetics CONTENTS 7.1 Chromosomes 7.1.1 Common sex chromosome aneuploidies 7.1.2 Common autosomal chromosome aneuploidies 7.1.3 Microdeletion syndromes 7.2 Mendelian inheritance 7.2.1 Autosomal dominant conditions 7.2.2 Autosomal recessive conditions 7.2.3 X-linked conditions 7.2.4 Genetic heterogeneity 7.3 Molecular genetics 7.3.1 DNA (deoxyribonucleic acid) 7.3.2 RNA (ribonucleic acid) 7.3.3 Polymerase chain reaction 7.3.4 DNA sequencing: the changing landscape of genetic testing 7.4 Trinucleotide repeat disorders 7.4.1 Fragile X syndrome 7.5 Mitochondrial disorders 7.6 Genomic imprinting 7.7 Other important genetics topics 7.7.1 Cancer genetics 7.7.2 Ambiguous genitalia 7.7.3 Cystic fibrosis 7.7.4 Neurofibromatosis 7.7.5 Tuberous sclerosis 7.7.6 Marfan syndrome Genetics 7.1 CHROMOSOMES Within the nucleus of somatic cells there are 22 pairs of autosomes and one pair of sex chromosomes. Normal male and female karyotypes are 46,XY and 46,XX, respectively. The normal chromosome complement is known as diploid. Genomes with a single copy of each chromosome are known as haploid, and those with three copies of each chromosome are known as triploid. A karyotype with too many or too few chromosomes, in which the total is not a multiple of 23, is called aneuploid. Chromosomes are divided by the centromere into a short ‘p’ arm (‘petit’) and long ‘q’ arm. Acrocentric chromosomes (13, 14, 15, 21, 22) have the centromere at one end. Lyonisation is the process in which, in a cell containing more than one X chromosome, only one is active. Selection of the active X is usually random and each inactivated X chromosome can be seen as a Barr body on microscopy. Mitosis is diploid-to-diploid cell division (Figure 7.1). This occurs in somatic cells, resulting in two diploid daughter cells with nuclear chromosomes that are genetically identical both to each other and to the original parent cell. Meiosis is diploid-to-haploid cell division (Figure 7.2). This occurs in the germ cells of the gonads and is also known as ‘reduction division’. It results in four haploid daughter cells, each containing just one member (homologue) of each chromosome pair. Meiosis involves two divisions (meiosis I and II). The reduction in chromosome number occurs during meiosis I and is preceded by exchange of chromosome segments between homologous chromosomes called crossing over. All four daughter cells are genetically different, due to recombination from these crossovers. In males, the onset of meiosis and spermatogenesis is at puberty. In females, replication of the chromosomes and crossing over begins in fetal life, but the oocytes remain suspended before the first cell division until just before ovulation. Figure 7.1 Mitosis Figure 7.2 Meiosis Translocations • • • • Reciprocal: exchange of genetic material between non-homologous chromosomes Robertsonian: fusion of two acrocentric chromosomes at their centromeres (eg 14;21) Unbalanced: if chromosomal material has been lost or gained overall Balanced: if no chromosomal material has been lost or gained overall. 7.1.1 Common sex chromosome aneuploidies Turner syndrome (karyotype 45,X) This affects 1 in 2500 live-born girls but it is a frequent finding among early miscarriages. Patients are usually of normal intelligence, but may experience specific cognitive difficulties, particularly with arithmetic and visuospatial tasks. They have streak ovaries which result in primary amenorrhoea, low oestrogen with high gonadotrophins and infertility. Normal secondary sexual characteristics may develop spontaneously or be induced with oestrogens. Short stature throughout childhood with failure of the pubertal growth spurt is typical. Final height can be increased by early treatment with growth hormone. Cardiovascular complications are very common, with up to 50% having congenital heart disease, particularly coarctation. Type 2 diabetes and hypertension are common late-onset complications, and aortic dilatation and rupture are also observed, which contribute to the excess mortality in this condition. Other features may include those in the box. Features of Turner syndrome • Webbed or short neck • Shield chest with widely spaced nipples Renal abnormalities (eg horseshoe kidney, duplicated ureters, renal aplasia) in approximately • 30% • Cubitus valgus (wide carrying angle) • Low hairline • Autoimmune conditions, particularly coeliac disease • Non-pitting lymphoedema in approximately 30% When women with Turner syndrome are fertile, this is often due to the presence of 45,X/46,XX mosaicism. Their offspring may be at increased risk for 45,X (or other sex chromosome aneuploidy) and trisomy 21. Triple X syndrome (karyotype 47,XXX) Incidence of this karyotype is hard to estimate because patients show little phenotypic abnormality, but tend to be of tall stature, usually above the 75th centile. Intelligence is typically slightly reduced compared with siblings, by on average 10–15 IQ points, and therefore usually still falls within normal or low-to-normal limits. Speech delay is more common than in 46,XX; there may be higher chances of 47,XXX girls needing some help with this or other schooling needs (but usually in a mainstream school). Fertility is normal, but the incidence of premature ovarian failure is increased. There is a low risk of recurrence in offspring. Klinefelter syndrome (karyotype 47,XXY) This affects 1 in 600 newborn boys. Phenotypic abnormalities are rare prepubertally, other than a tendency for tall stature. At puberty, spontaneous expression of secondary sexual characteristics is variable but poor growth of facial and body hair is common. The testes are small in association with azoospermia, testosterone production of around 50% of normal and raised gonadotrophin levels (hypergonadotrophic hypogonadism). Gynaecomastia occurs in 30% and there is an increased (but still not high) risk of male breast cancer. Female distribution of fat and hair and a high-pitched voice may occur but are not typical. Intelligence is generally marginally reduced compared with siblings but usually falls within normal or low-to-normal limits. Mild developmental delay (especially speech) and behavioural problems are more common. 47,XYY males This occurs in approximately 1 in 1000 newborn boys. These boys are phenotypically normal but tend to be tall. Intelligence is usually within normal limits but there is an increased incidence of behavioural abnormalities. Fertility is usually normal, with a low risk for recurrence in offspring. 7.1.2 Common autosomal chromosome aneuploidies In general, trisomy is tolerated better by the organism than monosomy. There are no whole autosome monosomies that are compatible with life. It is no coincidence that the three autosomal aneuploidies compatible with live birth involve the three least gene-rich chromosomes. Down syndrome (trisomy 21) Down syndrome affects 1 in 700 live births overall and is usually secondary to meiotic nondisjunction during oogenesis, which is more common with increasing maternal age. Of patients, 2% have an underlying Robertsonian translocation, most commonly between chromosomes 14 and 21. This arises anew in 50% and is inherited from a parent in 50%. Around 3% of people with trisomy 21 have detectable mosaicism (a mixture of trisomy 21 and karyotypically normal cells), usually resulting in a milder phenotype. Phenotypic features of Down syndrome • • • • • Brachycephaly Protruding tongue Single palmar crease, fifth finger clinodactyly, wide sandal gaps between first and second toes Upslanting palpebral fissures, epicanthic folds, Brushfield’s spots on the iris Hypotonia and moderate learning disability The next box shows the more common features in patients with Down syndrome. Common features of Down syndrome • Cardiovascular malformations in 40%, particularly atrioventricular septal defects (AVSDs) Haematological abnormalities, particularly acute lymphoblastic leukaemia (ALL), acute • myeloblastic leukaemia (AML) and transient leukaemias • Gastrointestinal abnormalities in 6%, particularly duodenal atresia and Hirschsprung’s disease • Hypothyroidism • Cataracts in 3% • Alzheimer’s disease in most by age 50 years Edwards syndrome (trisomy 18) This typically causes intrauterine growth retardation, a characteristic facies, prominent occiput, overlapping fingers (second and fifth overlap third and fourth), rockerbottom feet (vertical talus) and short dorsiflexed great toes. Malformations, particularly congenital heart disease, diaphragmatic hernias, renal abnormalities and dislocated hips, are more common. Survival beyond early infancy is rare and associated with profound learning disability. Patau syndrome (trisomy 13) Affected infants usually have multiple malformations, including holoprosencephaly and other central nervous system (CNS) abnormalities, scalp defects, microphthalmia, cleft lip and palate, post-axial polydactyly, rockerbottom feet, renal abnormalities and congenital heart disease. Survival beyond early infancy is rare and associated with profound learning disability. 7.1.3 Microdeletion syndromes These are caused by chromosomal deletions that are too small to be seen microscopically but involve two or more adjacent genes. They can be detected using specific fluorescent probes (fluorescent in situ hybridisation [FISH]), but may now more frequently be identified through array comparative genomic hybridisation or other methods of genome-wide testing. The following are examples of microdeletion syndromes: DiGeorge syndrome: parathyroid gland hypoplasia with hypocalcaemia, thymus hypoplasia with T-lymphocyte deficiency, congenital cardiac malformations (particularly outflow tract abnormalities such as interrupted aortic arch and truncus arteriosus), cleft palate, learning • disability; arises due to microdeletions at 22q11. There is an increased incidence of psychiatric disorders, particularly within the schizophrenic spectrum. Importantly, deletions may be inherited from phenotypically normal parents, demonstrating the variable effects of this deletion Williams syndrome: supravalvular aortic stenosis, hypercalcaemia, stellate irides, learning disability and chatty, sociable behaviour known as a ‘cocktail party manner’; caused by • microdeletions involving the elastin gene on chromosome 7. These deletions occur anew, because people with Williams syndrome are unlikely to have their own children. 7.2. MENDELIAN INHERITANCE 7.2.1 Autosomal dominant conditions Autosomal dominant (AD) conditions result from mutation of one copy (allele) of a gene carried on an autosome. Each child of an affected person has a 50% chance of inheriting the mutation. Within a family the severity may vary (variable expression) and known mutation carriers may appear clinically normal (reduced penetrance). Some conditions, such as achondroplasia and neurofibromatosis type 1, frequently begin anew through new mutations arising in the egg or (more commonly) in the sperm. Examples of autosomal dominant conditions* • • • • • • • • • • • • Achondroplasia Ehlers–Danlos syndrome (most) Facioscapulohumeral dystrophy Familial adenomatous polyposis coli Familial hypercholesterolaemia Gilbert syndrome Hereditary non-polyposis colorectal cancer Huntington’s disease Marfan syndrome Neurofibromatosis type 1 Neurofibromatosis type 2 Osteogenesis imperfecta (most) Porphyrias (except congenital erythropoietic and erythropoietic protoporphyria which are • autosomal recessive) • Tuberous sclerosis • Von Willebrand’s disease *Conditions prefixed ‘hereditary’ or ‘familial’ are usually autosomal dominant. An important exception is hereditary haemochromatosis which is autosomal recessive (see section 7.2.2). Noonan syndrome This is an AD condition with an unknown incidence, which may affect around 1 in 2500 people. Around two-thirds of patients are the first affected person in their family. It is genetically heterogeneous, ie mutations at more than one gene locus can cause the Noonan phenotype. In around half the patients, the condition is caused by mutations in the PTPN11 gene (protein tyrosine phosphatase non-receptor type 11) on chromosome 12. Mutations in several other genes (coding for other proteins that are members of the MAPK kinase pathway) have recently been identified in Noonan syndrome, whereas the genetic basis of the syndrome in some individuals still remains unclear. As for other single gene disorders, the karyotype would be expected to be normal. Clinical features of Noonan syndrome • Cardiac • Pulmonary valve stenosis • Hypertrophic cardiomyopathy • Septal defects (ASD, VSD) • Branch pulmonary artery stenosis • Musculoskeletal • Webbed or short neck • Pectus excavatum or carinatum • Wide-spaced nipples • Cubitus valgus • Short stature in 80% • Other features • Poor feeding and hypotonia in infancy • Ptosis • Low-set and/or posteriorly rotated ears • Small genitalia and undescended testes in boys • Coagulation defects in 30% particularly factors XI:C, XIIC and VIIIC deficiencies) • Von Willebrand’s disease • Juvenile myelomonocytic leukaemia (rarely) • Thrombocytopenia • Mild intellectual disability in 30% 7.2.2 Autosomal recessive conditions Autosomal recessive (AR) conditions result from mutations in both copies (alleles) of an autosomal gene. Where both parents are carriers, each of their offspring has a one in four (25%) risk of being affected, and a 50% chance of being a carrier. Examples of autosomal recessive conditions • • • • • • • • • • • • Alkaptonuria Ataxia telangiectasia Congenital adrenal hyperplasia Crigler–Najjar syndrome (severe form) Cystic fibrosis Dubin–Johnson syndrome Fanconi’s anaemia Galactosaemia Glucose-6-phosphatase deficiency (von Gierke’s disease)a Glycogen storage diseases Haemochromatosis Homocystinuria • • • • • • • • • Mucopolysaccharidoses (all except Hunter syndrome) Oculocutaneous albinism Phenylketonuria Rotor syndrome (usually) Sickle cell anaemia Spinal muscular atrophy β-Thalassaemia Wilson’s disease Xeroderma pigmentosum Most metabolic disorders are autosomal recessive – remember the exceptions: X-linked recessive exceptions: Hunter syndrome (mucopolysaccharidosis or MPS type 2), glucose-6-phosphate dehydrogenase deficiency (favism) and the childhood form of adrenoleukodystrophy. Ornithine transcarbamoylase deficiency, a urea cycle disorder, also • shows X-linked inheritance, with affected males often having a severe neonatal onset, whereas carrier females may remain well into later life. They may, however, be at significant risk for dangerous hyperammonaemia in periods of stress or starvation Autosomal dominant exceptions: acute intermittent porphyria, variegate porphyria, familial • hypercholesterolaemia aDo not confuse with glucose-6-phosphate dehydrogenase deficiency (favism) which is X-linked recessive Hereditary haemochromatosis As stated previously, ‘hereditary’ or ‘familial’ conditions are usually autosomal dominant. However, hereditary haemochromatosis is autosomal recessive, due to mutation in the HFE gene, C282Y being much the most common mutation. The carrier frequency for this is high (>1 in 10), so pseudodominant inheritance has been observed. This occurs when the partner of an affected person is, coincidentally, a carrier so that, on average, 50% of his or her offspring will have a genotype predisposing to clinical haemochromatosis. An apparent vertical (dominant) transmission may therefore be observed. Only a small proportion of patients with mutations on both alleles will ever become symptomatic, and the penetrance is higher in males than females. (See also Chapter 6, Gastroenterology and Chapter 13, Metabolic Diseases.) 7.2.3 X-linked conditions These conditions result from a mutation in a gene carried on the X chromosome and most commonly affect males, because they have just one copy of each gene on the X chromosome. X-linked inheritance is characterised by the following: • No male-to-male transmission (an affected father passes his Y chromosome to all his sons) Daughters of an affected male are obligate carriers (an affected father passes his X chromosome • to all his daughters) • Sons of a female carrier have a 50% chance of being affected and daughters have a 50% chance of being carriers. Females are usually unaffected by X-linked recessive conditions, but may have mild manifestations as a result of X-inactivation (Lyonisation). Many X-linked conditions do not fit neatly into a purely recessive or dominant pattern, but have more severe expression in males than females, for example: X-linked Alport syndrome, due to mutations in COL4A5, causes renal failure and deafness in boyhood. Carrier females may have haematuria from early in life, but generally remain clinically • well unless they develop hypertension (as happens in a third) or renal failure (up to 15%), and deafness, later in life Fragile X, a trinucleotide repeat disorder, causes significant learning disability in affected boys, but up to half of female full-mutation carriers (see section 7.4.1) also have some learning or • behavioural problems. These are usually, but not always, less severe than those seen in affected boys Fabry’s disease, in which the long-recognised, mainly cardiovascular and renal phenotype in • males is also seen in a milder form in significant numbers of female mutation carriers. These females have a reduced life expectancy compared with non-carriers as a result of the disease X-linked recessive inheritance Examples of X-linked recessive (XLR) conditions • • • • • • • • • • • Becker muscular dystrophy Duchenne muscular dystrophy Fabry’s disease Glucose-6-phosphate dehydrogenase deficiency (favism) Haemophilias A and B (Christmas disease) Hunter syndrome (MPS 2) Lesch–Nyhan syndrome Ocular albinism Red–green colour blindness Androgen insensitivity syndrome Wiskott–Aldrich syndrome Note that recent evidence shows an increased risk of cardiac complications in female carriers of Duchenne muscular dystrophy (10% lifetime risk of overt cardiac failure) and Fabry’s disease. This may warrant 5-yearly echocardiographic screening in asymptomatic individuals, and more frequently if symptoms are present. X-linked dominant conditions In X-linked dominant (XLD) conditions, both male and female mutation carriers are affected by a mutation in a gene on the X chromosome. Females are usually less severely affected because of lyonisation, and these disorders are frequently lethal in males, because they have only a single X chromosome. All offspring of an affected female have a 50% chance of being affected; however, if the condition is embryonically lethal in males, as is the case for disorders such as incontinentia • pigmenti, a skewed birth ratio may be observed, ie one affected female:one unaffected female:one unaffected male (and an excess of miscarriages may be observed, representing affected male conceptions). The following are examples of XLD conditions: • • • • Vitamin D-resistant rickets: this results from mutations in the PHEX (phosphate-regulating gene with homology to endopeptidases, X-linked) gene. This is a non-lethal condition, such that males and females are affected, and either may pass the mutated X chromosome on to their children Incontinentia pigmenti (IP): a disorder of girls causing vesicular skin lesions in infancy with variable hypodontia (small teeth), alopecia, and retinal and other abnormalities. This results from mutations in the NEMO (NFκB essential modulator) gene. Such mutations are embryonically lethal in males, meaning that only females are affected (and affected females may have increased rates of miscarriage, or affected male conceptuses) Periventricular nodular heterotopia: this is associated with epilepsy and occasional learning disability in females, and, similar to IP, with embryonic lethality in males. It results from certain mutations in the FLNA (filamin A) gene. Rett syndrome results from mutations in the MeCP2 (methyl CpG-binding protein 2) gene. This is a disorder of girls associated with developmental regression, progressive microcephaly, stereotypical hand movements and irregular breathing patterns. Males with MeCP2 mutations are exceptionally rare (due to embryonic lethality) and usually extremely severely affected. Such mutations generally arise anew in the individual, because Rett syndrome is a severe enough condition that affected individuals do not reproduce. 7.2.4 Genetic heterogeneity This means that there is more than one gene which, when mutated, causes a particular phenotype. Examples are given in Table 7.1. 7.3. MOLECULAR GENETICS 7.3.1 DNA (deoxyribonucleic acid) DNA is a double-stranded molecule composed of purine (adenine + guanine) and pyrimidine (cytosine and thymine) bases linked by a backbone of covalently bonded deoxyribose sugar phosphate residues. The two antiparallel strands are held together by hydrogen bonds, which can be disrupted by heating, and re-form on cooling. • Adenine (A) pairs with thymine (T) by two hydrogen bonds • Guanine (G) pairs with cytosine (C) by three hydrogen bonds 7.3.2 RNA (ribonucleic acid) DNA is transcribed in the nucleus into messenger RNA (mRNA), which is translated by ribosomes in the cytoplasm into a polypeptide chain. RNA differs from DNA in that: • it is single-stranded • thymine is replaced by uracil • the sugar backbone is ribose. 7.3.3 Polymerase chain reaction The polymerase chain reaction (PCR) is a widely used method for generating large amounts of DNA from very small samples. PCR can be adapted for use with RNA provided that the RNA is first converted to DNA. (For a more detailed account see Chapter 14, Molecular Medicine.) Table 7.1 The genetic heterogeneity of various conditions Condition Alport syndrome Autosomal dominant polycystic kidney disease Noonan syndrome Retinal dystrophies (retinitis pigmentosa) Tuberous sclerosis Long QT syndrome Hypertrophic cardiomyopathy Hereditary motor and sensory neuropathy (Charcot–Marie–Tooth disease) Hereditary non-polyposis colon cancer Hereditary breast and ovarian cancer Genes (modes of inheritance) COL4A5 (X-linked), COL4A4 and COL4A3 (AR and AD) PKD1, PKD2 (AD) PTPN11, others (AD) RHO (rhodopsin, accounts for 30% of cases, AR), 40 or more other genes (X-linked, AR and AD) TSC1, TSC2 (AD) Genes coding for ion channel proteins (AD or AR) Genes coding for components of the sarcomere (AD) PMP22 (AD), also several other genes (AD, AR and X-linked) Mismatch repair genes MLH1, MSH2, MSH6 and others (AD, remember reduced penetrance) BRCA1, BRCA2 (AD, remember reduced penetrance) AD, autosomal dominant; AR, autosomal recessive. 7.3.4 DNA sequencing: the changing landscape of genetic testing Traditionally, genetic testing has been laborious, with DNA of individual exons (or lengths of DNA up to approximately 1–2 kilobases or kb in length) being amplified in single PCR reactions and then sequenced using dideoxy (Sanger) sequencing. This made testing for mutations in large genes, and testing for genetically heterogeneous disorders, very difficult and expensive. Massively parallel sequencing technologies developed since the mid-2000s mean that many millions of bases of DNA can now be read in a single experiment, and the cost of sequencing has fallen dramatically as a result. This means that testing for genetically heterogeneous disorders such as hypertrophic cardiomyopathy or retinal dystrophy can now be achieved in a single investigation. Similarly, patients with undiagnosed conditions may now be offered sequencing of their whole exome (all the coding genetic material) to identify the mutation responsible for their phenotype. Although a major advance in the diagnostic repertoire, with implications for many branches of medicine, such sequencing requires significant infrastructure and bioinformatic expertise. 7.4 TRINUCLEOTIDE REPEAT DISORDERS (See also Chapter 14, Molecular Medicine.) These conditions are associated with genes containing stretches of repeating units of three nucleotides and include those shown in the box. Trinucleotide repeat disorders • • • • • Fragile X syndrome, X-linked Huntington’s disease, AD Spinocerebellar ataxia, AD Myotonic dystrophy, AD Friedreich’s ataxia, AR In normal individuals the number of repeats varies slightly but remains below a defined threshold. Affected patients have an increased number of repeats, called an expansion, above the diseasecausing threshold. The expansions may be unstable and enlarge further in successive generations, causing increased disease severity (‘anticipation’) and earlier onset, eg myotonic dystrophy, particularly congenital myotonic dystrophy following transmission by an affected mother. 7.4.1 Fragile X syndrome This causes learning disability, macro-orchidism and seizures, and is often associated with a cytogenetically visible constriction on the X chromosome. The inheritance is X-linked but complex. Among controls, there are between 6 and 55 stably inherited trinucleotide repeats in the FMR1 gene. People with between 55 and 230 repeats are said to be premutation carriers, but are unaffected by fragile X syndrome. During oogenesis in female premutation carriers, the triplet repeat is unstable and may expand into the disease-causing range (230 to >1000 repeats), known as a full mutation. All males and around 50% of females with the full mutation are affected by fragile X syndrome. The effects of being a premutation carrier do not usually include learning disability, but premutation carrier females are at increased risk of premature ovarian failure, compared with controls or full mutation carriers. Males with premutations are at risk (estimated at 3%) of developing fragile Xassociated tremor/ataxia syndrome, which includes symptoms of parkinsonism and cognitive decline, around 50 years of age. 7.5 MITOCHONDRIAL DISORDERS (See also Chapter 14, Molecular Medicine.) Mitochondria are exclusively maternally inherited, deriving from those present in the cytoplasm of the ovum. They contain copies of their own circular 16.5-kilobase genome, which contains genes for several respiratory chain enzyme subunits and transfer RNAs. Mitochondrial genes differ from nuclear genes in having no introns and using some different amino acid codons. Within cells there may be a mixed population of normal and abnormal mitochondria known as heteroplasmy. Different proportions of abnormal mitochondria may be required to cause disease in different tissues, known as a threshold effect. Disorders caused by mitochondrial gene mutations include the following: • MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes) • MERRF (myoclonic epilepsy, ragged red fibres) • Mitochondrially inherited diabetes mellitus and deafness Leber’s hereditary optic neuropathy (note that other factors also contribute, resulting in higher • penetrance in males). 7.6 GENOMIC IMPRINTING For most genes, both copies are expressed but, for some genes, either the maternally or the paternally derived copy is preferentially used, a phenomenon known as genomic imprinting. The best known examples are the Prader–Willi and Angelman syndromes, both caused by either cytogenetic deletions of the same region of chromosome 15q or by uniparental disomy of chromosome 15 (where both copies of chromosome 15 are derived from one parent with no copy of chromosome 15 from the other parent). Each of the above conditions is described in Table 7.2. Other well-recognised imprinting disorders include: • • • • Albright’s hereditary osteodystrophy Beckwith–Wiedemann syndrome Russell–Silver syndrome Familial paraganglionoma Albright’s hereditary osteodystrophy This results from deactivating mutations in the GNAS gene (α subunit of the adenylyl cyclasestimulating G-protein, Gs) on chromosome 20q13. Mutations on the maternally derived GNAS allele result in an associated pseudohypoparathyroidism. The typical clinical features are as follows: • Short adult stature with a tendency to obesity • Round facies • Mild-to-moderate learning disabilities Brachydactyly: short metacarpals, particularly fourth and fifth, and short distal phalanges • (particularly the thumb) • Ectopic ossifications. Table 7.2 Genomic imprinting: comparison between Prader–Willi and Angelman syndromes Prader–Willi Clinical Neonatal hypotonia and poor feeding Moderate learning disability Hyperphagia + obesity in late childhood Small genitalia Genetics Angelman ‘Happy puppet’, unprovoked laughter/clapping Microcephaly, severe learning disability Ataxia, broad-based gait Seizures, characteristic EEG 80% deletion on maternal chromosome 15 30% maternal uniparental disomy 15 (ie no 2–3% paternal uniparental disomy 15 paternal contribution) (ie no maternal contribution) Many of remainder due to mutations in UBE3A gene 70% deletion on paternal chromosome 15 Beckwith–Wiedemann syndrome This is due to abnormal imprinting of the IGF2/H19/p57KIP/KvLqQT1 gene cluster on chromosome 11p15. The following are the clinical features: • • • • • Large birthweight Neonatal hyperinsulinism causing hypoglycaemia Omphalocele (exomphalos) Hemihypertrophy Facial nevus flammeus Increased risk of childhood abdominal tumours (particularly Wilms’ tumour and • hepatoblastoma). Russell–Silver syndrome This condition has a prenatal onset with small stature and relative macrocephaly, very poor feeding is usual • Patients also have a triangular face, asymmetry and fifth finger clinodactyly • • Maternal uniparental disomy for chromosome 7 is seen in around 10% of cases, abnormalities of other imprinted regions are also observed. Familial paraganglioma In this condition, paragangliomas, including phaeochromocytomas and glomus jugulare tumours, occur throughout the body (most commonly in the head and neck). This is due to mutations in the SDHB, SDHC and SDHD genes, but the mutation causes disease only when it has been inherited from the father. This is because the maternally inherited allele is imprinted (ie inactivated), and hence will not cause disease in the individual who inherits a mutation from his or her mother (Figure 7.3). The inheritance pattern of these conditions is in itself autosomal dominant, ie there is a 50% chance of the disease genotype being inherited by each child. However, whether the mutant allele is expressed depends on the parental origin of the allele, as shown in Figure 7.3. Figure 7.3 Genomic imprinting 7.7 OTHER IMPORTANT GENETICS TOPICS This section includes short notes on conditions that form popular exam topics. See also homocystinuria (Chapter 13, Metabolic Diseases) and muscular dystrophy (Chapters 14, Molecular Medicine, and 16, Neurology). 7.7.1 Cancer genetics Details of the increasing number of inherited cancer predisposition syndromes now defined are beyond the scope of this chapter (see also Chapter 6, Gastroenterology, re polyposis syndromes, Chapter 4, Endocrinology, re multiple endocrine neoplasia syndrome, and Chapter 14, Molecular medicine, re Li Fraumeni syndrome), general points to remember are: • Nearly all have AD transmission (note the reduced penetrance, see below) Young age at diagnosis or unusual combinations of cancers raise the suspicion of a heritable • cancer predisposition syndrome Penetrance is often reduced, eg 80% risk of breast cancer in female carriers of BRCA1 or BRCA2 mutations; colorectal cancer risk in hereditary non-polyposis colon cancer (HNPCC) is • approximately 80% for males and 60% for females, with an approximately 50% risk of endometrial cancer in female HNPCC mutation carriers Even in a high-risk family, non-genetic lifestyle factors are important to an individual’s cancer risk, such as smoking, diet (fresh fruit and vegetables, in particular resistant starch for bowel cancer risk) and maintaining a healthy body weight. For breast cancer risk, hormonal factors are also very important: late age of menarche, early age at birth of first baby, breastfeeding for more • than 6 months and earlier menopause are all protective; being overweight, and combined oral contraceptive and hormone replacement therapy (HRT) use can all increase risk. In Gorlin syndrome (basal cell naevus syndrome), and other conditions predisposing to skin cancer, meticulous sun protection and avoidance of X-irradiation if at all possible is important The von Hippel–Lindau disease is nearly completely penetrant, ie it is unusual for a person who carries a mutation not to develop at least one feature of the condition (cerebellar or spinal • haemangioblastoma, retinal angioma, phaeochromocytoma or renal cell carcinoma; cystic lesions in the kidneys and pancreas also occur) Certain tumours are unusual enough to be almost pathognomonic for a certain syndrome, eg • transitional cell carcinoma of the renal pelvis in HNPCC, or sebaceous tumours in Muir–Torre syndrome (the name for HNPCC occurring with these skin tumours). Screening may be recommended for at-risk individuals in several cancer-predisposing conditions, including the following: • • • • HNPCC: colonoscopy every 18–24 months for proven mutation carriers/those at 50% risk (frequency of colon [and upper gastrointestinal endoscopy] screening for other conditions may vary) High-risk hereditary breast and ovarian cancer: mammography, MRI breast screening where available (benefits of ovarian screening not proven) Von Hippel–Lindau disease: annual renal ultrasound, urinary catecholamines, ophthalmic review, 2- to 3-yearly MRI of brain and spine Familial renal carcinomas: annual renal ultrasonography. Discussion of prophylactic treatment is indicated in certain conditions: Colectomy (as development of malignancy is almost inevitable) in familial adenomatosis polyposis (FAP) is often performed between 16 and 30 years (this does not usually need to be • considered in HNPCC, because surveillance colonoscopy with polypectomy successfully prevents cancers) Prophylactic mastectomy and oophorectomy may be chosen (after appropriate counselling) by • some women in high-risk breast cancer families. Oophorectomy reduces the risk of breast cancer as well as ovarian cancer Prophylactic chemoprevention, eg using tamoxifen, may now be indicated for certain subgroups • of women at high risk of breast cancer. 7.7.2 Ambiguous genitalia (See also intersex in Chapter 4, Endocrinology.) The 6-week embryo has undifferentiated gonads, Müllerian ducts (capable of developing into the uterus, fallopian tubes and upper vagina), Wolffian ducts (capable of forming the epididymis, vas deferens and seminal vesicles) and undifferentiated external genitalia (Figure 7.4). In the presence of a Y chromosome, the gonads become testes which produce testosterone and Müllerian inhibiting factor (MIF). Testosterone causes the Wolffian ducts to persist and differentiate and, after conversion to dihydrotestosterone (by 5α-reductase), masculinisation of the external genitalia. MIF causes the Müllerian ducts to regress. In the absence of a Y chromosome, the gonads become ovaries which secrete neither testosterone nor MIF. In the absence of testosterone the Wolffian ducts regress and the external genitalia feminise. In the absence of MIF, the Müllerian ducts persist and differentiate. The causes of ambiguous genitalia divide broadly into those resulting in undermasculinisation of a male fetus, those causing masculinisation of a female fetus, and those resulting from mosaicism for a cell line containing a Y chromosome and another that does not. They are summarised in Figure 7.5. Figure 7.4 Outline of the normal development of the reproductive tract and external genetalia Figure 7.5 Outline of the causes of abnormal genitalia 7.7.3 Cystic fibrosis This results from mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene and the ΔF508 mutation (deletion of three nucleotides coding for a phenylalanine residue) account for 75% of mutations in White individuals. Around 15% of cystic fibrosis mutations cannot be detected on routine molecular testing, which tests for the most commonly identified mutations. Such testing cannot therefore exclude a diagnosis of cystic fibrosis (see also Chapter 19, Respiratory Medicine), but sequencing of the whole CFTR gene may be able to demonstrate rare alleles. 7.7.4 Neurofibromatosis There are two forms of neurofibromatosis (NF) which are clinically and genetically distinct. Both demonstrate a high rate of new mutations, meaning that patients may not have a family history of the condition (Table 7.3). 7.7.5 Tuberous sclerosis There are at least two separate genes that cause tuberous sclerosis (TS), one on chromosome 9 (TSC1, hamartin) and the other on chromosome 16 (TSC2, tuberin). Table 7.3 Comparison of neurofibromatosis (NF) types 1 and 2 NF1 Major features ≥6 café-au-lait patches (CALs) NF2 Bilateral vestibular schwannomas Other cranial and spinal tumours, eg Axillary/inguinal freckling meningiomas Lisch nodules on the iris Cutaneous neurofibromas Subcutaneous neurofibromas Plexiform neurofibromas Lens opacities/cataracts Peripheral schwannomas Minor features Macrocephaly Short stature Complications Plexiform neuromas Optic glioma (2%) Other cranial and spinal tumours Pseudoarthrosis (especially tibial) Sphenoid wing dysplasia Renal artery stenosis Phaeochromocytoma Learning difficulties Scoliosis Spinal cord and nerve compressions Malignant change/sarcomas CALs (usually <6) Peripheral neurofibromas Deafness/tinnitus/vertigo Spinal cord and nerve compressions Malignant change/sarcomas Gene Chromosome 17 Chromosome 22 Birth incidence 1 in 2000 1 in 30 000 Clinical features of tuberous sclerosis • Skin/nails • Ash-leaf macules • Shagreen patches (especially over the lumbosacral area) • Adenoma sebaceum (facial area) • Subungual/periungual fibromas • Kidneys • Renal cysts • Neuroimaging • Intracranial calcification (periventricular) • Subependymal nodules • Eyes • Retinal hamartomas • Heart • Cardiac rhabdomyomas, detectable antenatally, usually regressing during childhood • Neurological • Seizures • Learning disability 7.7.6 Marfan syndrome This results from mutations in the fibrillin 1 gene on chromosome 15. Intelligence is usually normal. Of affected individuals, 25% are the first affected person in their family (due to a new mutation). Clinical features of Marfan syndrome • Musculoskeletal • Tall stature with disproportionately long limbs (dolichostenomelia) • Arachnodactyly • Pectus carinatum or excavatum • Scoliosis • High, narrow, arched palate • Joint laxity • Pes planus • Heart • Aortic root dilatation and dissection • Mitral valve prolapse • Eyes • Lens dislocation (typically upward) • Myopia • Skin • Striae • Pulmonary • Spontaneous pneumothorax • Apical blebs on chest radiograph • Radiological • Protrusio acetabulae • Dural ectasia on spinal MRI The diagnosis of Marfan syndrome is based on the modified Ghent criteria. These were revised recently to place greater weight on the cardinal clinical features of aortic dilatation and ectopia lentis, and to take into account the emerging spectrum of mutations in fibrillin-1 associated with disorders other than Marfan syndrome (e.g. familial ectopia lentis, and Weill-Marchesani syndrome). A systemic score is calculated according to the presence of musculoskeletal, radiological and skin findings, weighted according to their diagnostic specificity. For patients without a family history, the following four conditions meet diagnostic criteria for Marfan syndrome: • • • • aortic dilatation (Z score greater than or equalling 2) and ectopia lentis aortic dilatation (as above) and fibrillin-1 mutation* aortic dilatation and systemic score greater than or equalling 7 ectopia lentis and fibrillin-1 mutation.* For patients with a first-degree relative (parent, sibling or child) with Marfan syndrome • (according to the above scheme), the presence of either aortic dilatation, ectopia lentis, or a systemic score of greater than or equalling 7, is sufficient to meet diagnostic criteria. * indicates that the mutation in fibrillin-1 should be known to be associated with Marfan syndrome. Chapter 8 Genito-urinary Medicine and AIDS CONTENTS 8.1 Sexually transmitted infections 8.1.1 Gonorrhoea 8.1.2 Syphilis 8.1.3 Chlamydia infections 8.2 Basic epidemiology and virology of HIV/AIDS 8.2.1 Epidemiology 8.2.2 The virus 8.2.3 Seroconversion and the HIV antibody test Centers for Disease Control and Prevention (CDC) classification of 8.2.4 HIV/AIDS 8.3 Respiratory diseases associated with HIV/AIDS 8.3.1 Pneumocystis jirovecii (carinii) pneumonia (PCP) 8.3.2 Pulmonary tuberculosis 8.3.3 Other respiratory diseases in HIV/AIDS 8.4 Gastrointestinal diseases in patients with HIV/AIDS 8.4.1 Oral/oesophageal conditions 8.4.2 Diarrhoea/abdominal pain 8.4.3 Biliary and pancreatic disease 8.4.4 Anorectal conditions 8.5 HIV/AIDS-related neurological disorders 8.5.1 Direct neurotropic effects of HIV 8.5.2 Neurological infections 8.5.3 Ophthalmic disorders 8.6 Malignant disease in patients with HIV/AIDS 8.6.1 Kaposi’s sarcoma (KS) 8.7 HIV/AIDS-related skin disease 8.8 Drug therapies in HIV/AIDS patients 8.8.1 8.8.2 8.8.3 8.8.4 Specific therapy of common opportunistic infections Antiretroviral therapy Prognosis of patients with HIV/AIDS New strategies for reduction of HIV transmission Genito-urinary Medicine and AIDS 8.1 SEXUALLY TRANSMITTED INFECTIONS The incidence of sexually transmitted infections (STIs) has increased dramatically over the past 50 years, both globally and in the UK. As well as the more ‘traditional’ diseases such as syphilis and gonorrhoea, a wider spectrum of diseases transmitted by sexual contact has increasingly been recognised (eg oroanal transmission of enteric infections such as giardiasis and hepatitis A). Human immunodeficiency virus (HIV) infection arrived on the scene in the late 1970s. 8.1.1 Gonorrhoea Transmission is primarily sexual; there is a large asymptomatic reservoir, mainly pharyngeal, rectal and cervical. Neisseria gonorrhoea is a capsulated organism, and it therefore resists phagocytosis. In the UK, >10% of isolates show resistance to penicillin and quinolones. This has resulted in cephalosporins currently being the first-choice antibiotic in uncomplicated gonorrhoea, currently intramuscular ceftriaxone. Treatment should be guided by the appropriate antibiotic sensitivities of the gonococcal isolates. Disseminated (bacteraemic) infection is unusual but is more common in women. Responsible strains are nearly always highly susceptible to penicillin. Pharyngeal and rectal infection is often asymptomatic. Ophthalmia neonatorum is treated with systemic antimicrobials and appropriate eye drops. 8.1.2 Syphilis Transmission is primarily sexual, although it may be congenital or, rarely, by blood transfusion. Penicillin is the drug of choice, with tetracycline as an alternative option. Concurrent HIV infection may increase the risk of neurosyphilis, and extended courses of treatment are required. Diagnosis is by: Serology: two specific treponemal tests, enzyme immunoassay (EIA) and Treponema pallidum haemagglutination assay (TPHA) (would use a specific treponemal antigen), plus a quantitative • non-treponemal test, ie rapid plasma reagin (RPR) or Venereal Disease Reference Laboratory (VDRL). The latter are non-specific (cardiolipin antigen) and biologically false-positive results can be obtained in other conditions Dark-ground microscopy: of fresh material from chancres or lesions of secondary syphilitic • rash • Treponemal PCR (polymerase chain reaction): a molecular test used to diagnose early syphilitic ulcers. In early syphilis, during the secondary stage, there is haematogenous spread of treponemes, which can give the following clinical presentations: • • • • • • Mucocutaneous: widespread non-itchy rash affecting hands and feet, oral and anal mucosal erosions Lymphadenopathy: usually generalised, painless Neurological: syphilitic meningitis, cranial nerve palsies Ocular: anterior uveitis, retinitis Gastrointestinal: hepatitis, proctitis Rheumatological: polyarthritis, periostitis. 8.1.3 Chlamydia infections Non-gonococcal urethritis (NGU) due to Chlamydia trachomatis is the most common bacterial STI in the Western world. Serovars D to K are responsible. It is also a major cause of pelvic inflammatory disease in women (frequently silent) and prostatitis/epididymitis in men. Neonatal conjunctivitis and, more rarely, diffuse interstitial pneumonia are both complications of serovars D to K; infection is acquired by passage through an infected birth canal. • Trachoma (corneal scarring) is caused by serovars A, B and C Lymphogranuloma venereum (LGV) is due to serovars L1, L2 and L3 and is an emerging • cause of rectal infection and proctitis in men who have sex with men (MSM). Both neonatal pneumonia and conjunctivitis need systemic treatment with erythromycin. Tetracycline or azithromycin is the drug of choice for adults. Molecular diagnostic NAATs (nucleic acid amplification tests) have the advantage of a higher sensitivity over culture and EIA tests, in addition to less invasive sampling. The main disadvantage is culture confirmation and antibiotic sensitivities required in case of gonorrhoea-positive NAATs. Current NAATs for STIs: • • • • • Gonorrhoea: can be used on urine sample in men and vaginal swab in women Chlamydia trachomatis: urine in men and vaginal/cervical swab in women Herpes simplex virus: direct from ulcer sample able to type virus 1 or 2 Syphilis: primary anogenital ulcers or mucosal lesions of secondary syphilis Trichomonas vaginalis: swab test on vaginal sample in women. 8.2 BASIC EPIDEMIOLOGY AND VIROLOGY OF HIV/AIDS 8.2.1 Epidemiology HIV/AIDS is a global disease. Of the estimated 34 million people infected with HIV, 23 million (69%) are from sub-Saharan Africa. Figures from the World Health Organisation (WHO) also indicate an emerging epidemic in the former Soviet Union and eastern Europe. In the UK there were approximately 96 000 prevalent HIV patients in 2011. In 2011 there were 6280 newly diagnosed cases, with 50% presenting with late HIV disease (CD4 count <350 mm) and 25% with advanced HIV disease (acquired immune deficiency disease or AIDS; CD4 <200 mm). The following are the estimated routes of transmission in the current UK HIV population: • • • • Sexual intercourse between men (42%) Sexual intercourse between men and women (49%) – mainly acquired abroad Injecting drug abuse (2.7%) Blood and blood products (5%). Risk factors facilitating sexual transmission include: • • • • Seroconversion and advancing stage of disease Concurrent STIs, particularly ulcerative disease of the genitalia Hepatitis C co-infection High viral load. Maternofetal transmission occurs in 15–20% of non-breastfed and 33% of breastfed infants of patients with HIV/AIDS without medical intervention. The risk of transmission from mother to baby can be reduced by: Antiretroviral therapy (this can reduce transmission to only 0.5% if therapy is started before the third trimester) • Avoidance of breastfeeding • Delivery by caesarean section (if detectable VL at 36 weeks). • 8.2.2 The virus Human retrovirus is a member of the lentivirus family. It contains RNA that is transcribed to DNA via a reverse transcriptase enzyme. The main target sites of action of antiretroviral drugs are reverse transcriptases, proteases and integrases. There are two types of human immunodeficiency virus: • HIV-1: (previously known as HTLV III) is prevalent worldwide • HIV-2: is common in West Africa. Pathogenesis The HIV virus has tropism for the following CD4 cells: • • • • T-helper lymphocytes B lymphocytes macrophages central nervous system (CNS) cells. HIV infection causes progressive immune dysfunction, characterised by CD4 cell depletion. Impairment of immunity is primarily cell-mediated, but as the disease progresses there is general immune dysregulation. The following laboratory markers are associated with disease progression: Decreased CD4 lymphocyte count (normal >500/mm3 or 0.5 × 109/l). In the USA, a CD4 count of <200/mm3 is regarded as AIDS, irrespective of the presence of clinical disease High HIV viral load, using HIV polymerase chain reaction (PCR) assay (note that CD4 and HIV • viral load are the only markers monitored in clinical practice which help to predict progression as well as the response to treatment). • 8.2.3 Seroconversion and the HIV antibody test After inoculation, the window or seroconversion period can be up to 3 months; HIV antibody may not be detectable during this time. The HIV p24 antigen becomes detectable during seroconversion. Current fourth-generation antibody tests/p24 antigen tests can detect HIV-1 as early as a month after exposure. Approximately 30% of patients develop clinical seroconversion illnesses of variable severity, and which are often diagnosed retrospectively. HIV PCR (viral load) and p24 antigen are used to diagnose HIV infection during this window period, and they are then confirmed by a positive confirmatory panel of antibody tests. If the seroconversion illness is severe, then antiretroviral combination treatment should be used. Whether such early treatment improves long-term prognosis is unknown. Seroconversion illnesses • • • • • • • • Fever Malaise Diarrhoea Meningoencephalitis Rash Sore throat Lymphadenopathy Arthralgia Constitutional symptoms in early infection: • Fatigue, night sweats, diarrhoea, dry itchy skin 8.2.4 Centers for Disease Control and Prevention (CDC) classification of HIV/AIDS The CDC classification is adopted in the USA and most developed countries. HIV infection is not synonymous with AIDS – the latter is a stage of severe immunodeficiency characterised by opportunistic infections and/or tumour. CDC classification of HIV/AIDS • Stage 1 • Primary seroconversion illness • Stage 2 • Asymptomatic • Stage 3 • Persistent generalised lymphadenopathy • Stage 4a AIDS-related complex (ie advanced HIV disease, but having none of the features of stages • 4b–d) • Stages 4b–d AIDS: patient may have opportunistic infection or tumours, which are termed ‘AIDS • indicator’ illnesses 8.3 RESPIRATORY DISEASES ASSOCIATED WITH HIV/AIDS 8.3.1 Pneumocystis jirovecii (carinii) pneumonia (PCP) Pneumonia is the most common opportunistic infection and clinical presentation of AIDS. Pneumocystis jirovecii (carinii) pneumonia (PCP) constitutes 40% of all AIDS-defining illness. The symptoms of PCP include dry cough, dyspnoea, fever and malaise. There are remarkably few abnormal signs on chest examination. Investigations for PCP Chest X-ray: the typical appearance of PCP is bilateral mid- and lower zone interstitial shadowing. Atypical chest X-ray findings are found in 10% of PCP cases and include: cavitation, • upper zone opacities, pneumothorax or unilateral consolidation. The chest X-ray may be normal and effusions are rare Pulse oximetry: hypoxia with low/normal PCO2 is typically seen in moderate-to-severe • infection. If O2 saturation is normal, then exercise-induced oxygen desaturation (O2 saturation falling by >5% and/or to a saturation of <90%, with exercise) will support the diagnosis of PCP Identification of pneumocystis cysts: samples obtained by inducing sputum or from • bronchoalveolar lavage (BAL) can be stained with silver or immunofluorescent antibody, or molecular detection tests such as PCR 3 • The combination of an HIV-positive person (usually with CD4 <200/mm ) who is not taking PCP prophylaxis and who has a typical radiological appearance and hypoxia is sufficient for a confident diagnosis to be made. Empirical treatment with co-trimoxazole should be started. It is now unusual to have to resort to lung biopsy for PCP diagnosis. Poor prognostic features in PCP include poor response to treatment, co-infection, requirement for assisted ventilation and pneumothorax. Treatment for PCP Treatment is with high-dose co-trimoxazole or intravenous pentamidine for severe cases. Clindamycin/primaquine, atovaquone and dapsone/trimethoprim are alternative treatments Intolerance to co-trimoxazole is common, with nausea, vomiting, rash, leukopenia and • thrombocytopenia • Steroids have been shown to improve prognosis in those with PO2 <8 kPa (60 mmHg) • There is a 50% risk of recurrence within 12 months. PCP prophylaxis (co-trimoxazole, nebulised pentamidine, dapsone or atovaquone) is always given to patients with a CD4 count <200/mm3 and to those who have already had an episode of PCP. Prophylaxis is continued until the CD4 count is increased above 200/mm3 with the use of highly active antiretroviral treatment (HAART). 8.3.2 Pulmonary tuberculosis The incidence of infection depends upon the prevalence of tuberculosis (TB) in the rest of the general population and it is therefore much more common in African patients. In some areas of the UK up to a quarter of patients with TB are HIV positive. Atypical features include: • Extrapulmonary involvement • Normal or atypical appearances on chest X-ray • Occurs at any stage of HIV disease, and at any level of CD4 count Atypical mycobacterial infections (when CD4 count <50/mm3) – usually Mycobacterium avium • intracellulare. The usual presenting features are fever, anaemia, anorexia and the disease is commonly extrapulmonary. 8.3.3 Other respiratory diseases in HIV/AIDS Other causes of respiratory disease in HIV/AIDS • Viral • Cytomegalovirus (CMV) pneumonitis • Fungal • Candida • Histoplasmosis • Cryptococcus • Nocardia • Bacterial • Streptococcus pneumoniae • Staphylococcus aureus • Mycobacterium tuberculosis • Mycobacterium avium intracellulare • Protozoal • Toxoplasma • Tumour • Kaposi’s sarcoma (see Section 8.6.1) • Non-Hodgkin’s lymphoma Radiological appearance of other infections • Cavitation: M. tuberculosis, Nocardia, S. aureus • Consolidation: S. pneumoniae, Toxoplasma • Effusion: TB (Kaposi’s sarcoma may also cause effusion). 8.4 GASTROINTESTINAL DISEASES IN PATIENTS WITH HIV/AIDS There are four main presentations: • • • • oral/oesophageal disease abdominal pain/diarrhoea biliary/pancreatic disease anorectal symptoms. 8.4.1 Oral/oesophageal conditions Ninety per cent of patients will develop an oral/oesophageal condition: • • • • • • oral and oesophageal candidiasis periodontal disease (including gingivitis) herpes simplex lymphoma oral hairy leukoplakia (caused by EBV) aphthous ulcers • Kaposi’s sarcoma • cytomegalovirus. These conditions may be asymptomatic, or patients may have dysphagia or odynophagia. 8.4.2 Diarrhoea/abdominal pain Weight loss, diarrhoea and malnutrition are very common in patients with any stage of HIV infection, and can be due to specific infection or advanced disease. Approximately 50% of diarrhoeal illnesses are infective in origin (due to specific enteropathogens or opportunistic infections). Enteropathogens found in HIV • Bacteria • Salmonella • Shigella • Protozoal • Giardia lamblia • Viral • CMV • Opportunistic organisms • Bacterial • Atypical mycobacteria (M. avium intracellulare with CD4 <100/mm3) • Protozoal • Isospora belli • Cryptosporidia (intracellular protozoan) • Microsporidia Clinical presentation can be with watery diffuse diarrhoea as exemplified by Cryptosporidium, or abdominal pain and bloody diarrhoea (eg CMV proctocolitis). Cryptosporidiosis: this is a coccidian parasite of the gastrointestinal tract which is responsible • for 10–15% of HIV-associated diarrhoeas, particularly occurring in patients with advanced HIV disease Salmonella: much more frequent in HIV-infected patients than in the general population. More • likely to cause bacteraemia, and recurrence is common. The investigation of infective diarrhoea includes the following: Identification of organisms in stool samples: microscopy and culture for pathogens, ova and parasites • If stool specimen negative, stain with modified Ziehl–Neelsen for Cryptosporidium • • Sigmoidoscopy/colonoscopy with biopsy: with culture or PCR detection of the specimen for viruses, mycobacteria, bacteriology and mycology. Histological appearances are often important. Gastrointestinal tumours These may also cause abdominal pain and diarrhoea. • Kaposi’s sarcoma: may cause rectal bleeding • Intra-abdominal lymphoma (often high-grade non-Hodgkin’s B-cell lymphoma). 8.4.3 Biliary and pancreatic disease The two most common presentations are cholangiopathy and pancreatitis. • Cholangiopathy: due to Cryptosporidium, CMV, or Microsporidium Pancreatitis: this can be induced by drugs used in HIV treatment (eg DDI (didanosine), or DDC • (zalcitabine), which are both reverse transcriptase inhibitors), or by the biliary organisms listed previously. 8.4.4 Anorectal conditions These usually present with proctitis. Symptoms and infective causes of anorectal conditions • Symptoms • Anal discharge • Tenesmus • Pruritus ani • Rectal bleeding • Diarrhoea • Causative organisms • Herpes simplex virus • Cytomegalovirus • Neisseria gonorrhoeae (gonorrhoea) • Non-specific/Chlamydia • Wart virus • Treponema pallidum (syphilis) • Chlamydia serovars 1–3, LGV 8.5 HIV/AIDS-RELATED NEUROLOGICAL DISORDERS Neurological disease is the first presentation of AIDS in 10% of HIV patients. An acute self-limiting lymphocytic meningitis may occur at the time of seroconversion. Chronic neurological syndromes or opportunistic infections occur later in the course of HIV infection. The most common cause is the neurotropic effect of the virus itself. Clinical presentation may be: • Focal: hemiparesis, fits • Generalised: drowsiness, confusion, behavioural change • Asymptomatic: in early HIV disease. Patients may also develop proximal myopathy, or drug-induced neuropathy (eg didanosine) and myopathy (eg zidovudine). 8.5.1 Direct neurotropic effects of HIV These include: • AIDS dementia complex (see below) • vacuolar myelopathy • neuropathy (see below) Neurotropic disorders are diagnosed with the help of: • CSF analysis: raised protein, and pleocytosis • MRI brain scan: cerebral atrophy • Nerve conduction studies: distal symmetric sensory neuropathy. AIDS dementia is the most frequent neurological condition of HIV infection, and is directly caused by the virus. Impairment of concentration and memory leads to progressive decline in widespread cognitive function. Occasionally psychiatric symptoms may be prominent. The EEG shows generalised slowing with no specific features, and imaging demonstrates cortical atrophy. Sensorimotor neuropathy associated with HIV/AIDS usually has mild sensory symptoms and signs. Less commonly, a mononeuritis multiplex or a chronic painful myelopathy may develop. HIVassociated neurocognitive dysfunction (HAND) may present as minor cognitive impairment at all stages of infection. There is an association with detectable virus in cerebrospinal fluid (CSF), even in presence of full virological suppression in plasma. Consideration of CSF penetration of antiretroviral drugs is sometimes indicated. 8.5.2 Neurological infections Opportunistic infections of the CNS are common. Causes of focal neurological disease • Toxoplasma gondii • Cerebral abscess • Mycobacterium tuberculosis • Meningitis • Tuberculosis abscess Causes of generalised neurological disease • Cryptococcus neoformans • Meningitis • Virus family (papovavirus) • Progressive multifocal leukoencephalopathy • Cytomegalovirus • Encephalitis/retinitis • Peripheral neuropathy Specific CNS infections Cerebral toxoplasmosis is the most common CNS infection (90% of focal lesions) and occurs in 10% of AIDS patients. The organism is the crescentic trophozoite form of Toxoplasma gondii. Investigations: CT brain scan shows solitary or multiple ring-enhancing lesions. Toxoplasma IgG serology is positive in >90% of cases First-line anti-Toxoplasma therapy is pyrimethamine plus sulfadiazine (with folinic acid to • prevent bone marrow suppression) • Prognosis: 10% mortality with first episode; 25% of patients have residual neurological deficit • It is important to differentiate from primary CNS lymphoma causing a space-occupying lesion. • Cryptococcal meningitis is due to a ‘budding’ yeast; it occurs in 5–10% of AIDS patients. It presents with a subacute meningitic illness. • Cryptococcal antigen is present in blood and CSF in most cases • India ink stain: positive in 70% of CSF samples. Neurosyphilis: the coexistence of HIV and syphilis can result in aggressive and atypical neurosyphilis. Previous syphilis infection may reactivate. The following features are recognised: • myelopathy • retinitis • meningitis • meningovascular. Diagnosis: from syphilis serology (rising VDRL and TPHA) and CSF, although serology may be modified by immune dysfunction. Treatment: The first-line therapy is intramuscular procaine penicillin and oral probenecid for 17 days. 8.5.3 Ophthalmic disorders AIDS may affect the lids or any layer of the eye. Ophthalmic features of AIDS • • • • • • • • • • Molluscum contagiosum of lids Episcleritis and keratitis Uveitis Choroidal granulomata CMV retinitis Neuro-ophthalmic manifestations (eg cranial nerve palsies, optic neuritis, sequelae to CNS infection or space-occupying lesion) Kaposi’s sarcoma of the eyelids or conjunctiva Retinal changes: haemorrhages, cotton wool spots, oedema and vascular sheathing Toxoplasmosis: may develop acquired disease or reactivation of pre-existing disease Candida endophthalmitis Retinitis is common and may be caused by HIV itself (non-specific microangiopathy which is present in 75% of HIV patients) or by CMV. CMV retinitis usually occurs when the CD4 count is <50/mm3. This is the most common AIDSrelated opportunistic infection in the eye (occurring in 25% of patients). • Symptoms: blurred or loss of vision; floaters • Signs: soft exudates, and retinal haemorrhages • Prognosis: initially unilateral eye involvement; ultimately both eyes are affected. 8.6 MALIGNANT DISEASE IN PATIENTS WITH HIV/AIDS Despite the introduction of HAART, the incidence of malignant disease in patients with HIV/AIDS has increased in recent years. The most frequently occurring malignancies are: • Kaposi’s sarcoma (83%) • Non-Hodgkin’s lymphoma (13%) • Primary CNS lymphoma (4%) Other non-AIDS malignancies at increased risk are anal cancer and cervical cancer, both • associated with oncogenic HPV type 16/18. 8.6.1 Kaposi’s sarcoma (KS) This occurs in 10–15% of HIV patients as the first AIDS-defining presentation. The tumour is derived from vascular or lymphatic endothelial cells and is due to infection with human herpesvirus type 8 (HHV8). This virus is closely related to EBV and is transmitted sexually, vertically and via organ transplantation. Clinical presentation: Kaposi’s sarcoma (KS) can have cutaneous and visceral involvement. Lesions appear as purple plaques or nodules. The most common systems involved are the gastrointestinal tract (30% of patients with KS of the skin also have gastrointestinal • involvement), lymph nodes and the respiratory system. Patients with pulmonary KS have cough, dyspnoea and infiltrates, lymphadenopathy or effusion on chest X-ray. KS is now quite uncommon owing to the effect of the new antiretroviral combination therapies • Diagnosis: clinical appearance (or biopsy in difficult cases) Prognosis: depends on stage of sarcoma: tumour (T), extent of systemic involvement (ie gastrointestinal, pulmonary) and level of immune status, immunosuppression (I), as indicated by • level of CD4 lymphocyte count. The best prognosis occurs when disease is confined to skin or lymph nodes, when there is minimal oral disease, and when the CD4 lymphocyte count is >150/mm3. 8.7 HIV/AIDS-RELATED SKIN DISEASE Dermatological diseases are extremely common in HIV patients (affecting 75%), especially in those who have AIDS. During the acute HIV illness, patients may develop an asymptomatic maculopapular eruption affecting the face and trunk. During seroconversion, they may also develop marked seborrhoeic dermatitis. As the disease progresses to AIDS, the development of tumours and atypical infections is seen. Dermatological associations of HIV disease • General inflammatory dermatoses • Psoriasis • Eczema • Seborrhoeic dermatitis • Folliculitis • Fungal/yeast infections • Pityrosporum ovale* • Candidiasis* • Cryptococcus neoformans • Histoplasma capsulatum • Malignancy • Kaposi’s sarcoma • Lymphomas • Cervical intraepithelial neoplasia* • Viral infections • Herpes zoster/herpes simplex • Human papilloma virus* • Cytomegalovirus • Molluscum contagiosum* • Bacterial infections • Tuberculosis • Syphilis • Bacillary angiomatosis • Staphylococcus aureus *Features common in HIV patients. Other skin diseases that are recognised include: Generalised maculopapular rash (due to drugs): co-trimoxazole (25%), nevirapine (14%), efavirenz (4%), abacavir (5%), dapsone (5%) • Nail pigmentation: zidovudine, indinavir • Stevens–Johnson syndrome (due to drugs): nevirapine, co-trimoxazole. • 8.8 DRUG THERAPIES IN HIV/AIDS PATIENTS 8.8.1 Specific therapy of common opportunistic infections Opportunistic infections in HIV/AIDS and their treatment are outlined in Table 8.1. 8.8.2 Antiretroviral therapy Antiretroviral therapy is usually given as combination therapy with the following aims: • Suppression of viral replication to undetectable levels (<40 copies/ml) • Reducing the risk of viral resistance emerging with three or more drugs • Improving patient immunity with reduction of morbidity and mortality. Highly active antiretroviral treatment (HAART) This involves combinations of at least three drugs; for example, two different nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) in addition to a protease inhibitor (PI), or a non-nucleoside reverse transcriptase inhibitor (NNRTI). There are three main classes of antiretroviral drugs currently licensed in the UK. Their modes of action are by inhibition of the viral reverse transcriptase enzyme or by inhibition of protease enzymes. Table 8.1. Opportunistic infections, their treatment and side-effects in HIV/AIDS Infection First-line drugs Side-effects Pneumocystis pneumonia Rash, bone marrow toxicity, Co-trimoxazole (oral, or IV for nausea and fever moderate-to-severe infection) Hyper/hypoglycaemia, Pentamidine (IV) pancreatitis, hypotension Cerebral toxoplasmosis Pyrimethamine and sulfadiazine Bone marrow suppression, fever, (in combination) gastrointestinal reactions, rash Cryptococcal meningitis Amphotericin and flucytosine (in combination) Chills, fever, gastrointestinal reactions, renal impairment (amphotericin), bone marrow toxicity, liver toxicity CMV retinitis Ganciclovir or valganciclovir Foscarnet Cidofovir Bone marrow suppression Renal impairment Nephrotoxicity • Between 20% and 25% of ward admissions in patients with known HIV are due to drug toxicity Patients who fail combination therapy switch to salvage regimens, which might include drugs • from all classes (sometimes combinations of four to six drugs are used). Reverse transcriptase inhibitors Nucleoside/nucleotide analogues (NRTI): zidovudine, lamivudine, didanosine, abacavir, tenofovir • Non-nucleoside analogues (NNRTI): efavirenz, nevirapine, etravirine, rilpivirine Protease inhibitors (PI): these act by inhibiting a protease that is needed to make the virus • viable outside the cell. Particular PIs include saquinavir, ritonavir, fosamprenavir, lopinavir, atazanavir, darunavir. • Other drugs used as antiretrovirals Interleukin-2: this is used to boost CD4 counts in those patients who have had good HIV • suppression with therapy, but who have failed to recover CD4 counts. The agent has little effect on HIV viral load Enfuvirtide (T-20): amino acid peptide (GP41) competes with the HIV viral envelope protein • for fusion to the cell membrane (therefore, a fusion receptor inhibitor). This is used in conjunction with HAART salvage therapy. Newer antiretroviral drug classes currently licensed for use • Integrase inhibitors (inhibit cellular integration of viral DNA), eg raltegravir and elvitegravir • CCR5 inhibitors (classed as entry uptake inhibitors), eg maraviroc. Side-effects of antiretroviral drugs • Nucleoside/nucleotide analogues • Zidovudine: myopathy, anaemia, fatigue, bone marrow toxicity, nail changes • Tenofovir: renal tubular dysfunction • Lamivudine: peripheral neuropathy, fatigue • Abacavir: hypersensitivity reaction (can be fatal on rechallenge) • Didanosine: pancreatitis, peripheral neuropathy • Non-nucleoside analogues All agents: potential for drug interactions via the CYP450 cytochrome family; they can act as • inhibitors or inducers • Nevirapine: rash, hepatitis • Efavirenz: rash, vivid dreams, hallucinations and depression • Protease inhibitors All agents: diabetes, hypertriglyceridaemia and hypercholesterolaemia (except atazanavir), central adiposity, buffalo hump, peripheral fat loss (lipodystrophy syndrome also associates • with nucleoside analogues, eg zidovudine and stavudine); there is also great potential for drug interaction via the CYP450 cytochrome family (ritonavir is the most potent inhibitor known) • Atazanavir: no effect on lipids, but hyperbilirubinaemia occurs in 5% Monitoring of HIV patients on treatment • • • • • • Clinical assessment: examination of mouth (for ulcers and candidiasis), skin, lymph nodes, chest, fundoscopy and weight Renal and hepatic function CD4 lymphocyte count HIV viral RNA load Viral resistance assay HLA-B5701 – a genotypic allele which is carried in up to 4–6% of the population (lower in African origin ˜1%) which can predict severe abacavir hypersensitivity • Cholesterol, blood sugar, triglycerides Lactate if symptoms of lactic acidosis (muscle pains, malaise, gastrointestinal symptoms, • breathlessness) are present Adherence to treatment: >90–95% of therapy must be taken to maintain adequate viral suppression, and this will also reduce the chance of resistance developing to therapy. If there is • evidence of virological failure (increased viral load on >2 tests), then HIV resistance testing is indicated. The latter involves viral genotype assay of point mutations associated with antiretroviral resistance to specific drugs • R5 tropism assay: genotype to assess suitability for CCR5 uptake inhibitors. 8.8.3 Prognosis of patients with HIV/AIDS HIV was previously the leading cause of death in the USA in people aged 25–40 years (40 deaths/100 000). The prognosis of HIV/AIDS patients has now been revolutionised by HAART (introduced 1997) and the death rate has reduced. • • • • • Life expectancy may surpass 25 years after diagnosis; can now be same as in uninfected individuals if HAART is started promptly (nadir CD4 count >350 mm) The new antiretroviral agents also significantly reduce mother-to-baby transmission of the virus from 20% to <1% (if breastfeeding is avoided) Individual prognosis depends on viral resistance (10% of new infections in Europe involve a resistant virus), side-effects and adherence to treatment; prognosis is worse if treatment is started when the CD4 count is below 200 cells/mm3 Evidence from the SMART Study suggests that the optimum time to commence HAART is when the CD4 count falls to around 350/mm3. Prognosis is worse in patients who present late with AIDS (mainly heterosexuals who may have no obvious risks); death is due to delay in diagnosis Coronary heart disease, end-stage liver failure (due to co-infection with hepatitis B and C) and malignancy (lymphoma) are now common causes of death in patients with HIV/AIDS. HIV has now become a treatable chronic illness rather than a fatal disease. 8.8.4 New strategies for reduction of HIV transmission Post-exposure prophylaxis after sexual exposure (PEPSE): a short course of antiretrovirals • (4 weeks of Truvada [emtricitabine/tenofovir]/Kaletra [lopinavir/ritonavir]) is taken within 72 h of ‘high-risk’ exposure and may reduce transmission by 70–80% Pre-exposure prophylaxis (PrEP): in high-risk, non-infected individuals, long-term adherence • to HIV drugs (Truvada) may reduce acquisition of HIV, but is limited by adherence and tolerability Treatment as prevention (TAP): virological suppression on ARVs can significantly reduce risk • of transmission to an uninfected discordant partner (96% in heterosexual couples), and can now be recommended in asymptomatic patients with higher CD4 counts Expanded HIV testing: to reduce late diagnosis in areas of high HIV prevalence (>0.2%), it is • recommended that routine testing should be offered across medical admissions and newly registered GP patients. Such early diagnosis will encourage behavioural and therapeutic interventions felt to reduce the burden of the global HIV epidemic. Chapter 9 Haematology CONTENTS 9.1 Anaemias 9.1.1 Definition and clinical features 9.1.2 Causes of macrocytosis 9.1.3 Causes of microcytosis 9.1.4 Red cell morphology 9.1.5 Sickle cell disease 9.1.6 Thalassaemias 9.1.7 Aplastic anaemia 9.2 Iron metabolism 9.2.1 Assessment of iron status 9.2.2 Sideroblastic anaemia 9.3 Haemolysis 9.3.1 General features and causes of haemolysis 9.3.2 The antiglobulin (Coombs’) test 9.3.3 Microangiopathic haemolytic anaemia 9.3.4 Paroxysmal nocturnal haemoglobinuria 9.4 Measurement of inflammation 9.4.1 Erythrocyte sedimentation rate 9.4.2 C-reactive protein 9.4.3 Plasma viscosity 9.5 White cell disorders 9.5.1 Leukocytosis 9.5.2 Leukoerythroblastic change 9.5.3 Neutropenia 9.6 Haematological malignancies 9.6.1 9.6.2 9.6.3 9.6.4 9.6.5 9.6.6 9.6.7 9.6.8 9.6.9 9.6.10 9.6.11 9.6.12 9.6.13 Leukaemias Specific chromosome abnormalities in leukaemia/lymphoma The French–American–British morphological classification of acute leukaemia Chronic myeloid leukaemia Chronic lymphocytic leukaemia Hodgkin’s lymphoma Non-Hodgkin’s lymphoma Myeloma Monoclonal antibodies in the treatment of haematological diseases Polycythaemia Thrombocytosis Myelodysplasias Stem cell transplantation 9.7 Coagulation 9.7.1 The coagulation mechanism and detection of coagulation factor deficiencies 9.7.2 Haemophilias 9.7.3 Von Willebrand’s disease 9.7.4 Disseminated intravascular coagulation 9.7.5 Vitamin K-dependent coagulation factors (II, VII, IX, X) 9.7.6 Thrombocytopenia 9.8 Thrombosis 9.8.1 Venous thrombo-embolism (VTE) prophylaxis 9.8.2 Thrombosis and the pill 9.8.3 Thrombophilia 9.8.4 Therapeutic fibrinolysis 9.8.5 Low-molecular-weight heparin 9.8.6 Direct-acting oral anticoagulants 9.9 The spleen 9.9.1 Causes of splenomegaly 9.9.2 Splenectomy 9.9.3 Causes of hyposplenism 9.10 Blood transfusion 9.10.1 Better blood transfusion 9.10.2 Transfusion-transmitted infection 9.10.3 Platelet transfusion in marrow failure 9.10.4 Indications for the transfusion of fresh frozen plasma Haematology 9.1 ANAEMIAS 9.1.1 Definition and clinical features Anaemia is defined as a reduction in the concentration of circulating haemoglobin. The British units of haemoglobin measurement changed from grams per decilitre (g/dL) to the SI units of grams per litre (g/L) in 2013; the decimal point has moved one place to the right but the numbers are otherwise unchanged. The normal haemoglobin level varies with age and sex, neonates having higher levels than adults, infants lower levels and women having lower levels than men. Clinical features of anaemia • Pallor – examine mucous membranes • Decreased oxygen-carrying capacity (shortness of breath on exertion, tiredness) Increased cardiac output (palpitations, ‘haemic’ ejection murmurs, cardiac failure in elderly • people) Unless the cause of anaemia is known it is usually classified by red cell size using the mean (red) cell volume (MCV), each type of anaemia being associated with a different list of differential diagnoses: • Macrocytic: large red cells • Normocytic: normal size red cells • Microcytic: small red cells. 9.1.2 Causes of macrocytosis Normal maturation of erythroid cells is termed ‘normoblastic erythropoiesis’. Many causes of macrocytic anaemia are associated with a series of morphological changes in the bone marrow, which include a lacy appearance to the nuclear chromatin of developing erythroblasts, premature appearance of haemoglobin in their cytoplasm (pink colour), giant metamyelocytes and (in the blood) hypersegmented neutrophils. Put together these changes are termed ‘megaloblastic erythropoiesis’. Causes of macrocytosis with megaloblastic erythropoiesis Vitamin B12 deficiency: vitamin B12 is found in liver, red meat and fish, and bound to intrinsic factor secreted by the parietal cells of the stomach. This delivers it to the absorption receptors in • the terminal ileum. Measurement of holocobalamin-bound or ‘active’ vitamin B12 is a more reliable predictor of deficiency than total vitamin B12, much of the latter being irreversibly bound to carrier proteins Folic acid deficiency: folic acid is found in fruit and vegetables (‘foliage’), destroyed by • cooking, absorbed in the jejunum. Measurement of red cell folate provides a longer look back at folate status than serum folate which reflects only recent folic acid intake Drugs affecting bone marrow nucleic acid synthesis: methotrexate, hydroxycarbamide, • azathioprine and many other chronically administered cytotoxics. Causes of vitamin B12 deficiency • Lack of intake: vegans • Lack of intrinsic factor: pernicious anaemia, gastrectomy Lack of absorption ability: inflammatory bowel disease affecting the terminal ileum, surgical • resection of terminal ileum Competitive consumption (rare): colonisation of small bowel by bacteria that consume vitamin • B 12 Pernicious anaemia • • • • • • • The most common cause of macrocytic anaemia, often positive family history for autoimmune disorders and more frequent in northern races Autoimmune attack against gastric parietal cells that secrete intrinsic factor and acid May be associated with other autoimmune disorders such as vitiligo or myxoedema Vitamin B12 is required for nervous tissue so peripheral neuropathy, subacute combined degeneration of the cord, dementia and optic atrophy are associated Presence of intrinsic factor antibodies in serum strongly supports the diagnosis of pernicious anaemia (PA). Parietal cell antibodies are also commonly found but are not specific for PA Shilling test for B12 absorption is, sadly, no longer generally available in the UK Simple and cheap to treat with lifelong quarterly hydroxocobalamin B12 injections; anaemia improves in weeks/months but neurological damage may take years. Causes of folic acid deficiency • Lack of intake: poverty, crank diets • Lack of absorption: inflammatory bowel disease or surgical resection • Increased requirement: pregnancy, haemolytic anaemias Macrocytosis with a normoblastic bone marrow • • • • • High reticulocyte count: young cells are big cells. Most commonly seen in recovery from surgical blood loss and in haemolytic anaemias Liver disease: interference with hepatic manufacture of lipids for the red cell envelope, one cause of target cells on the blood film Alcohol: direct toxic effect of alcohol on the bone marrow; may also be a cause of liver disease and associated with dietary folate deficiency Myxoedema: check not due to the associated autoimmune disease PA! Pregnancy: usually mild. Macrocytosis associated with haematological diseases having their own special features • • • • Myelodysplasia: associated with cytopenias, monocytosis and dysplastic changes in blood and bone marrow cells, sometimes with increased myeloblasts if transforming to acute myeloid leukaemia Myeloma: look for paraprotein, high erythrocyte sedimentation rate (ESR), leukoerythroblastic blood picture Myeloproliferative disorders: polycythaemia (high haemoglobin, haematocrit, red cell count, white cell count), essential thrombocythaemia (high platelet count), myelofibrosis (anaemia, leukoerythroblastic film, teardrop poikilocytes), chronic myeloid leukaemia Aplastic anaemia: pancytopenia with low reticulocyte count and hypoplastic marrow. 9.1.3 Causes of microcytosis Iron deficiency: look for pencil cells, hypochromia (pale staining red cells), check serum iron/total iron-binding capacity (TIBC) or ferritin Thalassaemia trait: look for Mediterranean/Asian origin, check HbA2 level (elevated in most • cases of β thal. trait) Anaemia of chronic disease: often normocytic, usually obvious disease, and raised • inflammatory markers • Sideroblastic anaemia: the MCV may be low, normal or high (see Section 9.2.2). • 9.1.4 Red cell morphology Sometimes morphological changes reported on the blood film are sufficiently characteristic to suggest a diagnosis (Table 9.1). Dimorphic red cell populations The dimorphic red cell picture refers to the presence of two populations of red cells. These differ in cell size and/or staining intensity, and may be detected by modern blood counters and film examination. Causes are: • After transfusion of normal donor red cells into a patient with a microcytic or macrocytic anaemia Haematinic deficiency responding to treatment. The new normal cells contrast with the persisting • abnormal cells characteristic of the anaemia • Mixed deficiencies separated in time (eg folatedeficient patient then develops iron deficiency) In the early stages of primary sideroblastic anaemia the clone of abnormal erythroblasts may • produce abnormally sized red cells; these contrast with the persisting normal-sized red cells which are a product of normal erythropoiesis. 9.1.5 Sickle cell disease Haemoglobin consists of haem, an iron-containing part, and globin, a protein-containing part. Globin consists of two polypeptide chains. The normal human haemoglobins differ in the nature of these globin chains. At birth most haemoglobin is fetal Hb (HbF), containing two α and two γ globin chains. During the first year of life there is a gradual switch to production of adult haemoglobin (HbA) which contains two α chains and two β chains. Up to 3.5% of normal haemoglobin is the second adult haemoglobin HbA2, which contains two α chains and two β chains. Table 9.1 Characteristic morphological changes found in red cells Changes in shape (poikilocytosis) Teardrops Fragmented cells and helmet cells Pencil cells Elliptocytosis Sickle cells Found in Myelofibrosis Microangiopathic haemolysis Iron deficiency (with hypochromic microcytes) Hereditary elliptocytosis Sickle cell disease Changes in staining characteristics Polychromasia Any cause of haemolysis but particularly warm autoimmune haemolysis and hereditary spherocytosis Liver disease, post-splenectomy, iron deficiency, thalassaemias and haemoglobinopathies Young red cells, implying a high reticulocyte count, if this is measured Changes in arrangement of red cells Rouleaux Agglutinates Any cause of a high erythrocyte sedimentation rate Presence of cold agglutinins Spherocytes Target cells In the haemoglobinopathies one or other of the polypeptide chains of globin has an abnormal structure, eg in sickle cell disease valine is substituted for glutamic acid in position six of the β chain. In the thalassaemias the globin chains are normal in structure but one or other of them is not made in sufficient quantity. Sickle cell disease is the most common serious inherited disease in England; 13,500 suffer from the disorder and there are 240,000 carriers of sickle trait. The sickle cell diseases consist of homozygous sickle cell anaemia (HbSS), haemoglobin SC disease (HbSC), and haemoglobin S β-thalassaemia trait (HbSThal). More than two-thirds of cases of sickle cell disease are sickle cell anaemia. The clinical manifestations of sickle cell disease are caused by the occlusion of small blood vessels by logjams of sickled red cells, resulting in local tissue hypoxia and subsequent infarction. Precipitating causes may be hypoxia, dehydration and infection, but often no cause can be determined for a vasoocclusive crisis. Clinical syndromes found in sickle cell disease • • • • • • Simple pain crisis: due to infarction of red bone marrow, a common problem in sickle cell disease. Red marrow is active haemopoietic marrow, which in normal adults is confined to skull, sternum, spine and pelvis – in the axial skeleton of adults with haemolytic anaemia, the red marrow may extend into the long bones, and normal babies may have red marrow to their fingertips (see sickle dactylitis below). Deep-seated bone pain often requires opiate analgesia, preferably with diamorphine. Visual analogue scoring, patient-controlled analgesia, nonsteroidal anti-inflammatory drugs (NSAIDs) and nitrous oxide have a role to play. Vigorous hydration may shorten the duration of crisis and oxygen therapy should be given for hypoxaemia demonstrated by good quality pulse oximetry. Infection is treated with antibiotics after appropriate cultures have been taken Pulmonary infarction (chest syndrome): may be associated with infection. A serious complication of sickle cell disease often requiring exchange transfusion Localised areas of splenic infarction: results in pleuritic pain in the left hypochondrium often radiating to the left shoulder and may be associated with an audible rubover the affected area. The spleen is responsible for removing senescent red cells from the circulation at the end of their lifespan and the older the red cell the more likely it is to undergo irreversible sickling, so sickled red cells may accumulate in the splenic vasculature leading to local hypoxia and infarction. The spleen in most sickle cell patients atrophies by repeated infarction during childhood, resulting in hyposplenism (see Section 9.9) Vaso-occlusive stroke: a rare but serious complication of sickle cell disease requiring urgent and repeated exchange transfusion Priapism: painful sustained penile erection due to sickling of red cells in the corpora cavernosa, which may lead to long-term impotence. Perineal ice packs and walking up and down stairs may be helpful while waiting for urological opinion, and an exchange transfusion is often required Sickle dactylitis: infarction of the small bones of the hands or feet (which contain red active marrow in childhood) may be the earliest manifestation of sickle cell disease. Local pain and swelling result with possible long-term deformity Splenic sequestration crisis: in children the spleen and liver may rapidly enlarge (over hours) and become painful. This is associated with massive retention of sickled cells in the spleen, • resulting in severe anaemia with a requirement for urgent top-up transfusion. The bilirubin and reticulocyte count (already elevated in sickle cell disease) are higher than usual and the haemoglobin lower Aplastic crisis: this is a syndrome of severe anaemia with a lower reticulocyte count and bilirubin level than usual for the patient. It is usually due to parvovirus B19 infection (now renamed erythrovirus). In normal people this infection results in a mild febrile illness (‘slapped cheek’ or fifth disease), with infection of red cell precursors in the marrow causing a temporary • shutdown of red cell production. In patients with an increased red cell turnover, such as sickle cell disease, a precipitous drop in haemoglobin level may result from a short interruption of erythropoiesis. Aplastic crisis may be found in other congenital haemolytic anaemia associated with a high red cell turnover Other areas of sickle infarction: no tissue is immune. Infarction of the retina, particularly in haemoglobin SC disease may lead to retinal detachment and blindness. Infarction of the placenta • may lead to fetal loss and small-forgestation babies. Intractable leg ulcers are common in countries where protective footwear is not worn. Avascular necrosis of the head of femur may be seen in adults. Transfusion in sickle cell disease As the oxygen dissociation curve of HbS is shifted to the right in comparison with HbA, oxygen is more easily released from haemoglobin to the tissues. Anaemia is therefore well tolerated and red cell transfusion for the correction of anaemia is rarely required, except in aplastic or sequestration crises. For severe sickle problems, exchange transfusion with non-sickling, HbA-containing red cells is required. To be effective the percentage of HbA needs to be raised to 80–90% and care needs to taken not to increase the haematocrit, which may lead to stagnation, increased sickling and increased vascular occlusion. Using ABO-compatible red cells matched for Rhesus and Kell antigens will inhibit the development of atypical red cell antibodies which may otherwise complicate future transfusions. The following are commonly accepted indications for exchange transfusion: • • • • • Frequent severe sickle pain crisis Central nervous system sickling Priapism Chest syndrome not responding to conservative management Preoperatively or in pregnancy if there is a bad sickling history or a large operation is required. Haemoglobin F in sickle cell disease Elevated levels of HbF protect against sickling, hence clinical manifestations of sickle cell disease are not seen before 1 year of age, after which the physiological switch from HbF to HbS becomes complete. Hydroxycarbamide, an oral cytotoxic mainly used for the treatment of myeloproliferative diseases, has the side-effect of increasing HbF levels and is sometimes used for the amelioration of sickle cell disease; however, this use has to be balanced against its other possible effects of marrow suppression, reduction of fertility and teratogenicity. New drugs without these side-effects are in development. 9.1.6 Thalassaemias In these disorders the structure of the globin chains is normal, but not enough of the globin chains of haemoglobin can be produced. The disorder may affect α chains (α-thalassaemia) or β chains (βthalassaemia). Both types of thalassaemia may be severe (homozygous, major) or mild (heterozygous, trait). Thalassaemia is the most common inherited genetic disorder in the world, with 5% of the world population carrying α-thalassaemia and 1.5% β-thalassaemia trait. In England, there are approximately 215,000 carriers of β-thalassaemia trait and 1000 suffer from β-thalassaemia major. Thalassaemias orginate from the areas of the world with historically high incidence of malaria, but with increasing immigration, the incidence in Europe is increasing. Alpha-Thalassaemia Alpha chains are required for the production of HbF, HbA and HbA2. As α-chain production is controlled by four genes, various degrees of clinical severity can be seen. With one α gene affected there is a mild microcytosis without anaemia. Three α genes affected results in a microcytic/hypochromic anaemia with splenomegaly. In this situation, unpaired β chains may complex together to form a tetramer of β chains which is called HbH. HbH may be detected by routine haemoglobinopathy screening methods or seen in red cells stained by an incubated reticulocyte stain. When four α genes are affected, death in utero results. In β-thalassaemia major the blood is normal at birth, because β chains are not required for the production of fetal haemoglobin. During the first year of life there is failure to switch over from HbF to HbA production and the syndrome of anaemia, growth-stunting and hepatosplenomegaly arises. Management of β-thalassaemia major • • • • • Effective treatment depends on regular (every 3–6 weeks) blood transfusions of ABO, Rhesus and Kell–matched red cells, which leads to iron overload Iron overload results in cardiomyopathy, endocrine failure and cirrhosis, but can be prevented by iron chelation therapy. The aim of chelation therapy is to maintain the ferritin level <1000 μg/L Desferrioxamine: given by overnight subcutaneous infusion (using a syringe driver or balloon pump) on 2–5 nights of the week, depending on the degree of iron overload Deferasirox: an orally active iron chelator that removes iron mostly in the bile and faeces. As a result of its cost, it is available in the UK only for desferrioxamine treatment failures Inheritance of β-thalassaemia major is autosomal recessive. Screening for the heterozygous (trait) by blood count and haemoglobinopathy screening is performed routinely in pregnancy. Intrauterine diagnosis of thalassaemia major by chorionic villous sampling is possible, allowing the option of therapeutic abortion of an affected fetus. β-Thalassaemia trait The variable clinical presentation of α-thalassaemia has been remarked upon above. BetaThalassaemia trait is associated with minor suppression of β-chain manufacture and a mild microcytic/hypochromic anaemia with a haemoglobin usually >90 g/L. Besides assessing iron status (see Section 9.2.1), an elevated HbA2 level is a useful marker of this trait. 9.1.7 Aplastic anaemia This is a pancytopenia (reduction in white cell count, haemoglobin and platelet count) secondary to marrow hypoplasia. The reticulocyte count measured by high precision (automated) techniques is lower than normal. Aetiology of aplastic anaemia • Idiopathic: most cases are in fact autoimmune • Drugs: an idiosyncratic reaction to drugs such as gold, phenylbutazone and chloramphenicol Post-hepatitis: viruses that are toxic to hepatocytes may also kill bone marrow stem cells. The • aplasia may supervene after recovery from the hepatitis. As a predictable reaction to chemotherapy or radiation. About 1 in 300 of the general population has low levels of thiopurine methyl transferase (TPMT), the main enzyme responsible • for degradation of the immunosuppressants azathioprine and mercaptopurine. Measurement of serum TPMT allows suitable reduction in dose of these drugs to prevent severe myelosupression in deficient patients Management of aplastic anaemia • Remove possible causes (eg stop possible offending drugs) Supportive: red cell transfusion for the correction of anaemia, antibiotics for infections, platelet • transfusion for thrombocytopenia bleeding. Granulocyte colony-stimulating factor (G-CSF) does not improve stem cell numbers but may boost the numbers and function of maturing myeloid cells Immunosupression: usually with a combination of high-dose steroids, anti-lymphocyte globulin • and ciclosporin • Stimulation of residual bone marrow activity: anabolic steroids Bone marrow transplantation: in severe cases; most successful in children with an HLAmatched sibling. A reduced intensity conditioning regimen is used, avoiding the toxicity of total • body irradiation, because the bone marrow is already empty and there are no malignant cells to eradicate. 9.2 IRON METABOLISM A representation of the body’s iron economy is shown in Figure 9.1. Iron absorption may be greatly increased in iron deficiency, but iron excretion cannot be increased in the case of iron overload. Most iron in the body is contained within red cells, so chronic bleeding is a potent cause of iron deficiency. The marrow normally contains stainable iron stores, but it is possible to have no stainable iron in the bone marrow but a normal haemoglobin level. The converse is not true – in anaemia due to iron deficiency, the marrow will not contain stainable iron. In megaloblastic anaemias, haemoglobinopathies and myelodysplasia, red cells may die and enter the reticuloendothelial recycling system without leaving the bone marrow – this is termed ‘ineffective erythropoiesis’. Figure 9.1 Iron economy in the body 9.2.1 • • • • • Assessment of iron status Transferrin saturation: may be calculated by dividing the serum iron by total iron-binding capacity (TIBC) and multiplying by 100%. Neither the serum iron nor the TIBC is particularly helpful on its own, so transferrin saturation should always be requested. This is low in iron deficiency and high in iron overload Serum ferritin: a major transport and storage form of iron that is high in iron overload states and low in iron depletion. It is one of the acute phase proteins, and so, similar to C-reactive protein (CRP), fibrinogen and immunoglobulins, is released in inflammatory illness. If the ESR is increased then the ferritin may be falsely high. Ferritin is also released from damaged liver cells, and so will also be falsely elevated in the presence of a transaminitis Iron stain on bone marrow particles: this is the gold standard, but invasive and expensive, so rarely performed in the diagnosis of iron deficiency Serum-soluble transferrin receptor: the latest index for measuring iron status, being high in iron deficiency and low in iron overload. It is available only in some laboratories Trial of oral iron: In some patients it is difficult to establish the cause of an anaemia with certainty and a trial of oral iron for about a month is justified, and will do harm if the patient is not iron overloaded. Functional iron deficiency • Despite normal iron stores assessed by stainable marrow iron and normal serum ferritin, iron is not transferred to the developing erythroblast • Functional iron deficiency (FID) is a major contributor to the anaemia of chronic disease Inflammation causes increased levels of hepcidin, a polypeptide hormone made by the liver, to • be secreted. This prevents iron release from macrophages for use by developing red cells Diagnosis by specialist red cell indices – raised percentage of hypochromic red cells and low • reticulocyte haemoglobin content (CHr); also increased red cell zinc protoporphyrin level (ZPP) • FID results in failure to respond to erythroidstimulating agents such as erythropoietin Diagnosis of FID is an indication for intravenous iron supplementation, despite normal or raised • ferritin. 9.2.2 Sideroblastic anaemia In this disorder there is a failure to incorporate iron into the haemoglobin molecule, due to a biochemical block, and it accumulates in the mitochondrial factories. These become poisoned and are visible as iron granules lying in a ring around the erythroblast nucleus. Hence the diagnostic feature is ring sideroblasts in the bone marrow iron stain. Causes of sideroblastic anaemia • Congenital: rare, usually sex linked, responsive to pyridoxine • Acquired primary: one of the myelodysplastic disorders Acquired secondary: alcohol, malignancy in the body, drugs (eg anti-tuberculous), connective • tissue disorders, heavy metal poisoning Management of sideroblastic anaemia • Remove the cause if known High doses of pyridoxine and folic acid may act as a coenzyme in the incorporation of iron into • haemoglobin • Erythropoietin may improve the haemoglobin level • Red cell transfusion: this may worsen iron overload. 9.3 HAEMOLYSIS Destruction of red cells may occur in the: • circulation (intravascular) • reticuloendothelial system (extravascular). Mild intravascular haemolysis liberates haemoglobin from red cells which the body tries to conserve by binding to plasma proteins. Initially this will be haptoglobin, so haptoglobin levels will be reduced as the iron-laden haptoglobin is collected by the liver. Then albumin will bind free haemoglobin, forming methaemalbumin, which may be detected by a positive Schumm test. Without a protein to bind to, the haemoglobin will pass through the glomerulus to appear in the urine – haemoglobinuria. This will give a positive stick test for haemoglobin, but in contrast to haematuria, red cells will not be seen on urine microscopy. In extravascular haemolysis, the red cells are engulfed by macrophages mainly in the spleen and liver. In cases of severe haemolysis both mechanisms may occur together. 9.3.1 General features and causes of haemolysis The anaemia is commonly macrocytic and associated with: • Elevated reticulocyte count: >2% Jaundice: pre-hepatic, unconjugated, water-insoluble bilirubin, so not found in the urine. • However, urobilinogen may be found in the urine – due to increased breakdown products of porphyrins secreted into the bile and reabsorbed from the bowel. Detected by simple stick test • Abnormal red cell morphology: particularly spherocytes (see Section 9.1.4). Causes of haemolysis • Mainly intravascular • Immediate and some delayed haemolytic transfusion reactions • Paroxysmal cold haemoglobinuria • Microangiopathic haemolytic anaemia Red cell enzyme deficiencies including glucose-6-phosphate dehydrogenase deficiency and • phosphokinase deficiency • Infections – malaria (Blackwater fever) • Paroxysmal nocturnal haemoglobinuria • Mainly extravascular • Warm autoimmune haemolytic anaemia • Cold haemagglutinin disease • Haemolytic diseases of the newborn • Red cell membrane disorders: hereditary spherocytosis, elliptocytosis, pyropoikilocytosis • Some delayed haemolytic transfusion reactions • Haemoglobinopathies, eg sickle cell disease 9.3.2 The antiglobulin (Coombs’) test This is divided into direct and indirect tests. The direct antiglobulin test (DAT) detects antibody on the patient’s red cells. This coating may be as follows: Opsonising: making the reticulocytes attractive to the phagocytes of the reticuloendothelial system Complement fixing: causing a local enzymatic explosion, blowing a hole in the red cell • envelope Agglutinating: in which case the clumping of red cells may be visible in the blood sample vial • when it has cooled to room temperature, or on the blood film, without resorting to a DAT. • The indirect antiglobulin test detects antibody in the patient’s serum. This involves incubation of the patient’s serum with ABO-compatible test red cells bearing a variety of minor blood group antigens. This test is most frequently used as part of the ‘crossmatch’ or compatibility testing. Donor red cells are incubated with recipient plasma and, if there are incompatibility antibodies in the plasma, they will stick to the donor’s red cells and give a positive indirect antiglobulin test. 9.3.3 Microangiopathic haemolytic anaemia As might be expected from the name – micro (small), angio (blood vessel), pathic (disease of) – the essential mechanism of this condition is the laying down of fibrin strands in the capillary bed. These chop up passing red cells (similar to a wire cheese-cutter). If not too badly damaged these may reseal themselves and circulate as helmet (half) red cells or if multitudinously chopped, as fragmented cells. These may be seen on the blood film – the microangiopathic blood picture. All the usual features of intravascular haemolysis will also be present, including a reticulocytosis. Depending on the cause of the microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and consumption coagulopathy may also be present. Causes of MAHA • • • • • Disseminated intravascular coagulation (DIC) (see Section 9.7.4) Haemolytic uraemic syndrome (HUS) Thrombotic thrombocytopenic purpura (TTP) Malignant (accelerated phase) hypertension Severe pre-eclampsia Thrombotic thrombocytopenic purpura In addition to the general features of MAHA there is often fever, cerebral and cardiac dysfunction. Renal impairment is less marked than in HUS. (See also Chapter 15, Nephrology.) There is an excess of sticky high-molecular-weight von Willebrand’s factor in the plasma, which causes the platelets to adhere to vascular endothelium. This results in consumption thrombocytopenia and the blockage of small capillaries in the brain and kidney by platelet thrombi. Activation of the coagulation system causes fibrin strands to be laid down and these shred passing red cells, resulting in the classic features of microangiopathic haemolysis. In normal plasma, high-molecular-weight vWF is cleaved to less sticky vWF by a plasma protease, ADAMST13. Low levels of this protease (<10% of normal) have been found in many cases of TTP, and antibody directed against the protease has been demonstrated. In contrast to disseminated intravascular coagulation (DIC), the screening tests of coagulation (but not platelet count) are normal. ADAMST13 levels can be measured in plasma but this investigation is not commonly available enough to dictate initial management. Haemolytic uraemic syndrome HUS is the commonest cause of acute renal failure in childhood. It is most commonly caused by infection with shigatoxin-producing strains of enteropathogenic Escherichia coli 0157 due to contamination of food (particularly meat) or of hands by animal faeces (diarrhoea-associated HUS). When not associated with diarrhoea (about 10% of cases) it is termed atypical or diarrhoea-negative (aHUS) and is most commonly due to defects in the regulation of complement activation. Complementmediated damage to endothelial cells causes platelet activation and adhesion with laying down of fibrin strands that damage passing red blood cells - a microangiopathic picture identical to TTP. Atypical HUS may be sporadic or familial. Sporadic aHUS is commonly triggered by illness such as bacterial or viral infections, particularly Strep. pneumoniae. Most sporadic cases can be demonstrated to have a genetic predisposition due to mutations in complement regulatory proteins. Treatment of HUS Supportive therapy is the mainstay of treatment for diarrhoea-associated HUS, including maintenance of electrolyte balance and control of hypertension, with no particular role identified for antibiotic treatment unless the patient is clinically septic. Dialysis may be required with renal transplantation if the renal failure becomes irreversible. Atypical HUS is treated similarly to TTP, with highvolume plasma exchange. The anti-complement C5 monoclonal antibody eculizumab is effective (See PNH below) Treatment of TTP and HUS • • • • Large-volume infusion of fresh frozen plasma (FFP) (which contains the vWF-cleaving protease and complement components) is the mainstay of treatment, coupled with plasma exchange. The latter has the advantage of removing any antibodies and toxins involved in the pathogenesis of the disease. Cryo-poor FFP (from which cryoprecipitate, a useful blood product, has been removed) may be used for the plasma exchange and solvent-/detergent-inactivated FFP may confer less risk of transfusion-transmitted infection High-dose steroids may be of benefit in cases with an autoimmune aetiology and are often given (except in the epidemic form of HUS) Low-dose aspirin may be used to inhibit further adhesion of platelets to vascular endothelium once the platelet count has exceeded 50 × 109/L Rituximab, a monoclonal anti-CD20 antibody, is effective in cases with an autoimmune aetiology Other specific therapies may be required for specific disease sequelae (eg dialysis for acute • renal failure). 9.3.4 Paroxysmal nocturnal haemoglobinuria This is a rare acquired disorder that may affect all haematological cells. There is increased sensitivity of the cell membranes to the action of the patient’s own complement, which damages red cells, white cells, platelets and stem cells. This results in intravascular haemolysis with haemoglobinuria, leukopenia, thrombocytopenia and (sometimes) pancytopenia with a hypoplastic marrow – aplastic anaemia. The following are other clinical features: The release of tissue thromboplastin from damaged cells leads to an acquired thrombophilia when thrombosis may present in unusual sites such as the hepatic or portal veins. Paroxysmal • nocturnal haemoglobinuria (PNH) should be considered as an underlying diagnosis in the Budd– Chiari syndrome • There is an increased incidence of acute myeloid leukaemia. Pathogenesis and diagnosis of PNH A transmembrane glycoprotein is missing from the cell surface in PNH, and this ‘fence post’ would normally carry molecules that inactivate complement approaching the cell membrane. These molecules include the CD antigens CD55 and CD59, which are missing from the cell surface in PNH. This allows diagnosis by the immunophenotyping of red cells, white cells or platelets. Unlike many other causes of haemolysis, which may be associated with iron overload, iron deficiency is common in PNH because of chronic haemoglobin loss in the urine. A minor clone of PNH cells can be demonstrated by immunophenotyping of blood in haematological diseases associated with a ‘stressed’ marrow, such as aplastic anaemia. Treatment of PNH Red cell transfusion: the correction of anaemia often requires the use of washed red cells, as the transfusion of complement in the donor plasma may exacerbate haemolysis Anticoagulation: thrombosis is the most common cause of death, so anticoagulation with • warfarin is usual if the platelet count is >50 × 109/L Eculizumab: a monoclonal antibody directed against the complement component C5, this reduces haemolysis, rendering most patients transfusion independent, and decreases thrombosis. • As a result of its high cost, its use in the UK is limited to special PNH clinics who receive central funding Other therapies: erythropoietin, steroids and danazol are of unproven value, although folic acid • (and sometimes iron) supplements should be given. Bone marrow transplantation is curative but risky, and so usually reserved for patients developing acute myeloid leukaemia. • 9.4 MEASUREMENT OF INFLAMMATION Many medical disorders are associated with inflammation, and measurement of inflammatory markers is useful in screening for disease and following the clinical progress of inflammatory disease. The three most popular measurements are ESR, CRP and plasma viscosity. 9.4.1 Erythrocyte sedimentation rate An increased concentration of inflammatory proteins affects the dielectric of the suspending plasma so that red cells can approach each other more closely. Normally their surface negative electrical charge causes them to repel each other and remain in suspension. If they touch, they adhere face to face, forming stacks of red blood cells similar to piles of coins – rouleaux. These rouleaux may be seen on the blood film, when they suggest the presence of an inflammatory process or paraprotein. Alteration in the volume:surface area ratio means that rouleaux sediment more rapidly than individual red cells. When spherocytes are present, rouleaux cannot form, so the ESR may be falsely depressed. • • • • • • Despite the complex underlying mechanism, the ESR is a simple test to do and can be performed in the clinic using long, thin, citrated, bloodtaking tubes placed vertically in a rack. The ESR is measured as the depth in millimetres that the red cell meniscus has dropped after 1 hour The normal ESR is 2–20 mm/h. The normal range is age related, rising with advancing years. The upper limit for a normal ESR is often quoted as 0.5 × age in years for men and 0.5 × age + 5 in women. An ESR >100 mm/h is usually due to a paraprotein, collagen disease or tuberculosis There will be a delay of a few weeks, after cure of an inflammatory condition, before a return of the ESR to normal levels The ESR is not stable overnight in citrate tubes but EDTA (ethylenediamine tetra-acetic acid) (blood count) tubes can be used for up to 24 hours, provided that citrate anticoagulant is added in the laboratory at the time of the test The ESR is frequently used as a screening test to distinguish diseased from non-diseased patients – a normal ESR does not exclude disease, but an elevated one suggests an inflammatory process In the diagnosis of headache, a normal ESR does not exclude temporal arteritis, but an elevated one (usually >60 mm/h) supports the diagnosis. CRP may be more useful but is not always available as an out-of-hours investigation. 9.4.2 C-reactive protein The name refers to the original finding of a protein that reacted with the C-polysaccharide of pneumococci, but CRP is released by hepatocytes and fat cells in response to high levels of the cytokine interleukin-6 (IL-6) and appears to attach to dead and dying cells and bacteria, assisting in their removal by macrophages that bear receptors for CRP. The assay is relatively complex and performed in the laboratory. CRP levels rise in a few hours in response to inflammation and reach their peak in 2 days. CRP levels drop more rapidly than ESR as inflammation improves. A modest sustained elevation of CRP level is also a marker for increased cardiovascular risk. 9.4.3 Plasma viscosity Providing a viscometer is available this is a reliable and inexpensive way of assessing acute phase proteins, which include relatively large molecules such as fibrinogen and immunoglobulins. The sample is stable for several days at room temperature. 9.5 WHITE CELL DISORDERS 9.5.1 Leukocytosis An elevated white cell count may be due to an increase in any of the individual types of white cells in the blood and should prompt a differential count to determine whether there is a neutrophilia, lymphocytosis or, more rarely, an increase in the number of other white cell types causing the leukocytosis. The only types of white cell present in normal blood (in order of decreasing frequency) are neutrophils, lymphocytes, monocytes, eosinophils and basophils. Neutrophilia (>7.5 × 109/L) This is by far the most common cause of a leukocytosis. If acute it may be associated with young neutrophils (band cells, metamyelocytes) in the blood or ‘left shift’. Causes of neutrophilia • • • • • • Bacterial infections: localised or generalised Trauma Metabolic disorders: uraemia, acidosis, gout, eclampsia, poisoning Malignant neoplasms: particularly when associated with tissue necrosis Inflammation or infarction: myocardial infarction, burns, vasculitis Corticosteroid therapy Myeloproliferative disorders: chronic myeloid leukaemia, myelofibrosis, essential • thrombocythaemia, primary polycythaemia Lymphocytosis (>4.0 × 109/L) The morphology of the lymphocytes may give valuable clues, eg in acute viral infections the lymphocytes may show morphological abnormalities termed ‘reactive changes’, and in chronic lymphocytic leukaemia the mature-looking small lymphocytes characteristic of the disease are fragile and become crushed during the spreading of the blood film – ‘smear cells’. Causes of lymphocytosis • • • • Acute viral infections: influenza, glandular fever, rubella, mumps, acute HIV Chronic lymphocytic leukaemia Chronic infections: tuberculosis (TB), Brucella spp., hepatitis, syphilis Hyposplenism • Low-grade lymphomas with blood spill of lymphoma cells • A lymphocytosis is normal in infancy Eosinophilia (>0.5 × 109/L) In the developed world allergic disorders are the main cause of eosinophilia. Causes of eosinophilia • Allergies: asthma, hay fever, drug reactions • Skin diseases: eczema, psoriasis, dermatitis herpetiformis Parasite infections: most parasitic infections cause eosinophilia with the exception of malaria • and threadworm. ‘Tropical’ eosinophilia is usually the result of multiple parasitic infections Myeloproliferative disorders: as part of the granulocytosis of chronic myeloid leukaemia, and in • the rare myeloproliferative disorder associated with the FIP1L1/PDGRF translocation, which responds to imitanib • Neoplasms: Hodgkin’s lymphoma, interleukin-5-secreting T-cell lymphomas • Miscellaneous conditions: sarcoidosis, polyarteritis nodosa, eosinophilic granuloma Hypereosinophilia Prolonged eosinophilia from any cause may damage tissues mainly as a result of eosinophils degranulating toxic cationic proteins on endothelium and serous surfaces. In the heart, mural thrombi may form and be the source of systemic emboli. Chronic damage to the endocardium may lead to endomyocardial fibrosis. If the eosinophil count is chronically (>6 months) >1.5 × 109/L and the cause cannot be removed, consideration should be given to reducing it by steroid or hydroxycarbamide treatment and regular cardiac ultrasonographic assessments. Monocytosis (>0.8 × 109/L) Monocytes are tissue macrophages (‘dustbin lorries’) en route to the tissues to phagocytose and digest dead cells and other debris. Causes of monocytosis • Recovery from tissue-damaging procedures: chemotherapy, radiotherapy, trauma, surgery Chronic inflammatory disease: sarcoidosis, Crohn’s, ulcerative colitis, rheumatoid arthritis, • systemic lupus erythematosus (SLE) • Myelodysplastic syndromes including chronic myelomonocytic leukaemia Infections: TB, Brucella spp., kala-azar, typhus, bacterial endocarditis, malaria, Trypanosoma • spp. • Acute myelomonocytic leukaemia: when it will be associated with increased blast cells 9.5.2 Leukoerythroblastic change This is defined as the presence of nucleated red cells and primitive white cells of any type in the peripheral blood. There are two major causes: either the normal cells inhabiting the bone marrow are being evicted by a marrow infiltration or the patient has an acute severe illness. Causes of a leukoerythroblastic blood picture • Invasion of bone marrow space • Metastatic carcinoma: particularly breast, prostate, lung, kidney and thyroid • Haematological malignancy: leukaemia, lymphoma, myeloma, myelofibrosis • Lipid storage diseases: eg Gaucher’s • Bone disorders: eg osteopetrosis • Severe acute illness, eg massive trauma, septicaemia, severe haemolysis 9.5.3 Neutropenia This is defined as a neutrophil count of <2 × 109/L. Below <1 × 109/L some risk of bacterial infection exists, and <0.5 × 109/L may be severe and such patients, if in hospital, will usually be isolated and subject to a routine of neutropenia care, including prophylactic antiseptic mouthwashes, antifungal agents and avoidance of food with a high bacterial load. In the event of significant fever, a broadspectrum intravenous antibiotic regimen reserved for ‘febrile neutropenia’ is instituted. Causes of neutropenia • • • • • • • • Associated with intercurrent viral infection: usually mild neutropenia; reactive lymphocytes may be seen on the blood film Idiosyncratic drug reactions, eg clozapine, carbimazole Collagen diseases, eg SLE, rheumatoid arthritis Myelodysplasia: dysplastic changes such as hypogranularity or hypersegmentation often present After chemotherapy or radiotherapy Benign ethnic neutropenia: in Black or Arab individuals, whose neutrophils are held in the tissues rather than circulating in the blood Hypersplenism: usually a low platelet count and haemoglobin as well Marrow infiltration: usually associated with low platelet count and haemoglobin; sometimes a leukoerythroblastic blood picture 9.6 HAEMATOLOGICAL MALIGNANCIES These may be broadly divided into the following categories: • • • • leukaemias lymphomas myelodysplasias myeloproliferative disorders. Acute leukaemias are characterised by an excess of primitive blast cells in the marrow, spilling into the blood. Chronic leukaemias show an excess of more mature cells in the marrow and blood. In leukaemias, the malignant cells lie mainly in marrow and blood, whereas in lymphomas they lie mostly in lymph nodes. There is an overlap, however, so many cases of lymphoblastic lymphoma have marrow involvement by cells of the disease in addition to enlargement of lymph nodes and thymus. 9.6.1 Leukaemias Acute leukaemias • Acute myeloid leukaemia (AML) • Acute lymphoblastic leukaemia (ALL) Chronic leukaemias • Chronic myeloid leukaemia (CML) • Chronic lymphocytic leukaemia (CLL) Acute myeloblastic leukaemia • • • • • Predominantly affects adults Chemotherapy sufficient to induce marrow hypoplasia is usually required to induce remission Central nervous system (CNS) involvement rare More than 30% cure rate with chemotherapy May be further classified by morphological appearance (see below). Acute lymphoblastic leukaemia • Predominantly affects children • Remission may be induced by non-myelosuppressive chemotherapy • CNS involvement is common, requiring prophylactic intrathecal cytotoxic therapy • More than 80% cure rate with chemotherapy • Further classified by immunological surface markers. How to identify the leukaemic blast cell As treatment and prognosis differ between AML and ALL, it is important to be sure which disease it is. This may be determined by the following: Morphology: sometimes this is not helpful because lymphoblasts look similar to myeloblasts. • One give-away is the presence of Auer rods, stick-like crystallisations of myeloid granules that may be found in the cytoplasm of myeloblasts Immunological surface markers: particularly useful in ALL, allowing classification into T-cell, • B-cell and other immunological subtypes Cytochemistry: the leukaemic cells are stained for their biochemical activities. Important cytochemical tests in acute leukaemia are: Sudan black (stains lipid material in myeloblasts); • periodic acid–Schiff (PAS) (stains carbohydrate material in ALL); non-specific esterase (stains the monocytic variants of AML). Treatment strategies in acute leukaemia Chemotherapy treatment in acute leukaemia is usually divided into phases: Induction: inpatient chemotherapy designed to remove the bulk of leukaemic cells, allowing restoration of normal bone marrow function and remission (<5% blasts in the marrow) • Consolidation therapy: chemotherapy designed to remove residual leukaemia cells Maintenance chemotherapy: applied in ALL rather than AML – low doses of oral • chemotherapy given for 1–3 years. • Stem cell transplantation is a powerful treatment for acute leukaemia because it combines the leukaemia-killing effect of conditioning treatment with strong chemotherapy and radiotherapy, which removes all the recipient’s marrow cells with an immunological attack of the donor’s transplanted immune system against residual leukaemia (graft-versus-leukaemia effect). However, stem cell transplantation is a risky treatment, and this risk increases with age. Total body irradiation, often employed as a conditioning regimen, results in sterility. Powerful chemotherapy also carries major risks, so patients are stratified by risk of relapse. This allows the selective application of stronger, and hence riskier, chemotherapeutic regimens for those patients who require them, and less stringent chemotherapy in patients with a better prognosis (see below). Prognostic factors in acute leukaemias Acute lymphoblastic leukaemia • Age: <1 year or >10 years worsens prognosis; adults do particularly badly Height of highest pretreatment white cell count (a higher count = a higher tumour load and worse • prognosis, particularly in children) • Cytogenetics (see Section 9.6.2) • Sex – in children boys do worse • Immunophenotype (T-cell ALL usually has high presenting white cell count – see Section 9.6.3) Response to treatment is measured by blast cell count in the marrow, or by assessment of minimal residual disease (MRD). Morphological remission is defined as <5% blasts in the bone marrow. MRD assessment uses the polymerase chain reaction (PCR) to amplify clonal rearrangements of immunoglobulin genes (in B-cell ALL) or T-cell receptor genes (in T-cell • ALL) that are characteristic of that patient’s disease. PCR allows reliable detection of 1 leukaemic cell in 10,000 marrow cells, a sensitivity which cannot be approached by morphological examination. In children the persistence of more than one malignant cell per 104 marrow cells after 1 month into chemotherapy mandates the use of a more intensive chemotherapy protocol. Acute myeloid leukaemia • cytogenetics (see below) • age (over-60s do worse) • response to the first course of induction chemotherapy. 9.6.2 Specific chromosome abnormalities in leukaemia/lymphoma Cytogenetic abnormalities are found in two-thirds of cases of AML and three-quarters of cases of ALL. Chromosome abnormalities are important in leukaemia and lymphoma for the following reasons: • They act as a marker of the disease, indicating remission or relapse Some have a prognostic significance. If the prognosis is especially bad (eg Philadelphia chromosome in childhood ALL), then a high-risk treatment such as stem cell transplantation may • be employed early in treatment. If the prognosis is good (eg t(8;21) in adult AML), then conventional chemotherapy may be employed without a transplantation unless the patient relapses Some of the abnormal DNA sequences that result from chromosomal translocation can be • amplified by PCR to allow the detection of very small amounts of residual leukaemia, allowing adjustment of chemotherapy regimen (see MRD above). Many of the chromosomal abnormalities in leukaemia and lymphoma are translocations, involving the exchange of material between chromosomes (Table 9.2), eg t(9;22) involves a reciprocal translocation between chromosomes 9 and 22. Chromosome 22 comes off worse in this exchange, gaining only a small amount of extra material. The abnormally truncated short arms of this chromosome are recognisable as the Philadelphia chromosome (see Section 9.6.4). 9.6.3 The French–American–British morphological classification of acute leukaemia Acute leukaemia is associated with a massive increase in primitive blast cells in the marrow. Some of these cells may start differentiating along one of the myeloid pathways, and this can be assessed morphologically and is the basis of the French–American–British (FAB) classification. In ALL this has been largely supplanted by the immunophenotype. In AML there are eight morphological subtypes recognised as M0–M7. In general these are treated similarly, but two subtypes are worthy of special mention. Table 9.2 Cytogenetic abnormalities associated with malignant haematological disease Cytogenetic abnormality Found in t(9;22) t(15;17) t(8;21) Philadelphia chromosome (Ph) in CML – see section 9.6.4 Acute promyelocytic leukaemia (M3) – see section 9.6.3 AML with some differentiation (M2) – better prognosis Inversion of the long arm of chromosome 16 in acute myelomonocytic leukaemia inv 16 with bone marrow eosinophilia (AML M4Eo) – better prognosis (>47 chromosomes) childhood ALL – better prognosis Burkitt’s lymphoma (loss of Hyperdiploidy part of the long arm of chromosome 5) Myelodysplastic syndrome (refractory t(8;14) 5qanaemia) with abnormal megakaryocytes – lenalidomide-responsive t(14;18) Follicular NHL – found in three-quarters of cases ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CML, chronic myeloid leukaemia; NHL, non-Hodgkin’s lymphoma. Acute promyelocytic leukaemia (AML M3) Promyelocytic leukaemia is associated with DIC during the early phases of chemotherapy, as procoagulant granules are released from the dying abnormal promyelocytes. Heavy support with platelet transfusion and fresh frozen plasma is therefore required. • Most leukaemic cells are abnormal hypergranular promyelocytes • Auer rods and bundles of Auer rods (faggots) are common • Strongly Sudan black/peroxidise-positive The characteristic t(15;17) chromosome abnormality involves the retinoic acid receptor gene • (RARA) All-trans-retinoic acid (ATRA), a synthetic vitamin A analogue, can induce differentiation and • apoptosis of the promyelocytes, inducing remission without chemotherapy • Variant M3 is hypogranular but otherwise the same. Acute monocytic leukaemia (AML M5) • Morphological evidence of monocytic differentiation • Strongly non-specific esterase-positive • Often significant tissue infiltration of gums, liver/spleen, lymph nodes and skin • Release of the microbicidal enzyme lysozyme from the malignant cells damages the renal tubules, causing a potassium leak so that hypokalaemia may be found at presentation. 9.6.4 Chronic myeloid leukaemia CML is mainly a disease of middle age, with most patients presenting with tiredness, weight loss and sweating. Splenomegaly is found in 90% of cases. If the white blood cell count (WBC) is very high (>500 × 109/L) then problems associated with hyperleukocytosis may be found: visual disturbance, priapism, deafness, confusion. As with other myeloproliferative diseases, gout may be a presenting symptom. Treatment with tyrosine kinase inhibitors (particularly imatininb) has revolutionised the prognosis of this disease, and reduced in particular the frequency of transformation into an acute phase (blast crisis), which is very difficult to treat. The following are blood and marrow features of CML: • • • • • • • • • High white cell counts (100–500 × 109/L) Massive neutrophilia with left shift (ie some myelocytes, metamyelocytes) Absolute basophilia and eosinophilia Anaemia in relation to the height of the WBC Platelet count may be low, normal or high Increased blood colony-forming cells (stem cells) High serum vitamin B12 due to production of a vitamin B12-binding protein by the white cells BCR-ABL/Philadelphia chromosome, a diagnostic marker for the disease (see below) Marrow hyperplasia, sometimes with increased reticulin (fibrosis). Philadelphia chromosome and BCR-ABL The Philadelphia chromosome (Ph) is an abnormally truncated chromosome 22 that has lost part of its long arms, which have become attached to chromosome 9, with a much smaller portion of chromosome 9 being attached to 22. There is thus a translocation between chromosomes 9 and 22, termed t(9;22). More than 95% of cases have the Ph chromosome; the breakpoints are at the BCR gene on 22 and the ABL gene on 9. Most Ph-negative CML cases have a BCR-ABL translocation at the molecular level, although abnormal chromosome morphology is not present. Ph is also found in the following: • 5% of childhood ALL cases • 25% adult ALL cases • 1% adult AML cases. It carries a bad prognosis if found in these acute leukaemias. The protein product of the hybrid gene has tyrosine kinase activity. Treatment of CML The aims of treatment are as follows: • Clinical remission: reduction of hypercatabolic symptoms and splenomegaly • Haematological remission: normalisation of the blood count • Cytogenetic remission: disappearance of the Ph chromosome from marrow cells • Molecular remission: non-detectability of the BCR-ABL fusion gene by PCR. Tyrosine kinase inhibitors, of which the most used is imatinib, produce haematological remission in 90% of cases, cytogenetic remission in 60% and molecular remission in 20%. These results may improve with continued therapy. Hydroxycarbamide does not modify the underlying cytogenetic/molecular abnormality or prevent transformation into acute crisis, but is used to normalise the blood count and shrink splenomegaly while conformation of Ph status is being obtained. Quarterly measurements of blood BCR-ABL are usually performed, with excellent cytogenetic response being defined as a three log reduction in BCR-ABL percentage, ie <0.1% (assuming 100% at presentation). Patients who fail to respond to imatinib should be assessed for mutations of BCR-ABL associated with imatinib resistance and can be treated by the newer tyrosine kinase inhibitors such as dasatinib or nilotinib. The tyrosine kinase inhibitors are going through trials for the treatment of many other malignancies. Stem cell transplantation remains a curative option for young and fit patients who are not fully responsive to imatinib and who have a suitable donor. 9.6.5 Chronic lymphocytic leukaemia This is the most indolent of the chronic leukaemias. Many cases are discovered as an incidental finding when blood counts are done for some other reason, such as health screening. • The most common cause of a lymphocytosis in patients aged >60 years • Of cases, 95% are of B-cell lineage Diagnosis is confirmed by immunophenotyping – the cells express B-cell markers CD19 and • CD23, but paradoxically also express a T-cell antigen CD5 • The blood film shows mature-looking small lymphocytes with smear cells Progression is through lymphocytosis to lymphadenopathy, hepatosplenomegaly and marrow • failure, although patients may skip stages and this disease may remain unchanged for years Increased incidence of certain antibody-mediated autoimmune diseases, such as warm • autoimmune haemolytic anaemia and immune thrombocytopenia Treatment of CLL Many patients with CLL require no treatment, living at peace with their lymphocytosis to die of an unrelated complaint. Early antibiotic treatment of intercurrent infection is indicated because of the associated immunoglobulin deficiency, and some patients with recurrent infections may benefit from immunoglobulin administration, particularly during the winter months. Annual flu immunisation should be given. Chemotherapy is indicated for the following: • Patients with bulky disease or B symptoms (see under Hodgkin’s lymphoma below) • Cytopenias due to marrow infiltration • A short lymphocyte doubling time (ie rapid progression). If treatment is anticipated, an assessment of the p53 (tumour-suppressor) gene on chromosome 17p of the lymphocytes should be made by fluorescent in situ hybridisation (FISH). Deletions or mutations of p53 are associated with a worse prognosis and failure to respond to conventional chemotherapies such as chlorambucil, cyclophosphamide and fludarabine. • • • • • • Fludarabine, cyclophophamide and rituximab (FCR) is the most popular treatment option for fit patients who require therapy. Rituximab is a monoclonal anti-CD20 antibody. Fludarabine is highly immunosuppressive and pneumocystis prophylaxis with low-dose co-trimoxazole should accompany its use Single-agent oral chlorambucil or fludarabine may be used in less fit patients who will not tolerate the myelosupression of FCR High-dose methylprednisolone is effective at shrinking bulky disease and can be combined with rituximab Alemtuzumab, another monoclonal antibody directed against the CD56 antigen, is useful in cases with resistance to chemotherapy or demonstrated to have deletions or mutations of p53. It is effective at clearing marrow-based disease but less so for lymph-node disease. As the CD56 antigen is present on both T cells and B cells this treatment is very immunosuppressive and weekly monitoring for cytomegalovirus by PCR is appropriate Local radiotherapy will effectively shrink enlarged nodes causing a local problem Stem cell transplantation with reduced intensity conditioning may benefit young patients who require treatment and have a suitable donor The antibody-mediated autoimmune disorders are treated along conventional lines when they occur. 9.6.6 Hodgkin’s lymphoma The prognosis of Hodgkin’s lymphoma is related to clinical stage (Table 9.3), bulk of tumour and histopathological type. The clinical stage may be given the letter suffix A or B, to reflect presence or absence of systemic symptoms: • A: no ‘B’ symptoms B: B symptoms consist of significant fever (>38°C), night sweats (drenching), weight loss of • >10% in the last 6 months. Pruritis and alcohol-induced pain are not B symptoms, although they are useful indicators of relapse. Investigation • Many patients have neutrophilia, thrombocytosis and anaemia of chronic disease; some have an eosinophilia • The ESR and other inflammatory markers are elevated Lactate dehydrogenase (LDH) is elevated and provides a useful guide to volume of disease in • high-grade lymphomas; ‘bulky disease’ is a node mass >10 cm in diameter Clinical examination and CT are used to establish clinical stage; there is almost no role for • staging laparotomy if suitable imaging facilities are available Residual masses are common after treatment and it is often difficult to decide whether or not they • represent active disease. Positron emission tomography (PET) using radioactive glucose helps distinguish tissue that is metabolically active False-positive results may be found if the PET scan is performed within 6 weeks of completion • of chemotherapy, due to healing activity within the nodes. Table 9.3 Ann Arbor clinical staging of lymphomas Stage 1 One involved lymph node group Stage II Two nodal areas on one side of the diaphragm Stage III Lymph nodes on both sides of the diaphragm Stage IV Involvement of extranodal tissues such as liver or bone marrowa aThe spleen is an honorary lymph node, ie if involved this is not necessarily stage IV. Histological types of Hodgkin’s disease The Reed–Sternberg (RS) cell is the most useful diagnostic feature. This is a giant cell, often with twin mirror-image nuclei and prominent ‘owl’s eye’ nucleoli. Histological typing depends on the other cells within the diseased tissue: • • • • Lymphocyte-predominant: there is an infiltration with reactive T lymphocytes Nodular sclerosing (NS): bands of fibrous tissue separate nodules of Hodgkin’s tissue Mixed picture Lymphocyte depleted: no infiltrating lymphocytes. The prognosis worsens through the histological types from lymphocyte-predominant (best) to lymphocyte-depleted (worst). With the benefit of modern immunophenotyping methodology (which uses monoclonal antibodies) many cases of Hodgkin’s lymphomas that were historically classified as lymphocyte-predominant Hodgkin’s disease are now recognised to be non-Hodgkin’s lymphoma. More than two-thirds of cases of Hodgkin’s disease are of the NS type; this category can be subdivided into grade I and grade II NS Hodgkin’s lymphoma, depending on the number of RS cells and other histological features. Treatment Clinical stage I Hodgkin’s lymphoma can be treated with radiotherapy, and more advanced stages with combination chemotherapy. The dividing line depends on national and institutional preferences. Currently the most used used chemotherapy is ABVD which contains Adriamycin (doxorubicin), bleomycin, vinblastine and dacabazine. Many relapsed patients can be salvaged with second-line chemotherapy and stem cell autografts, particularly if the relapse occurs more than 1 year after completion of initial treatment. The most popular second-line chemotherapy is ESHAP (etoposide, cytosine arabinoside, methyl prednisolone [highdose steroid] and cisplatin). 9.6.7 Non-Hodgkin’s lymphomas Despite several international reclassifications of the histology, the categorisation of NHL remains in a state of flux. For clinical purposes the NHLs are divided into three groups: indolent, high grade and lymphoblastic. Indolent NHL • • • • • The cells are relatively mature and the disease pursues an indolent course without treatment. In many cases it is acceptable to watch and wait for symptoms or evidence of organ failure Local radiotherapy to involved nodal regions is effective and usually given in stage I disease (infrequent) because some patients can be cured by this Rituximab anti-CD20 monoclonal antibody is effective as most cases are of B-cell lineage. It is commonly given with other chemotherapy regimens for both aggressive and indolent B-cell lymphomas, and its addition usually improves the response by about 10% Single-agent chemotherapy (eg chlorambucil) is often used for diffuse disease Interferon may prolong remission duration. High-grade NHL • The cells are immature and the disease is rapidly progressive without treatment Combination chemotherapy is usual from the outset; the most used regimen is R-CHOP • (rituximab, cyclophosphamide, Adriamycin (hydroxydaunorubicin), vincristine (Oncovin) and prednisolone) It is usual to give four to eight (3-weekly) courses depending on the response, although bone • marrow suppression may cause a delay • Maintenance therapy with rituximab may be used • Multi-agent, alternating and hybrid regimens may be advantageous. Lymphoblastic NHL • The cells of the disease are very immature and have a propensity to involve the CNS • Treatment is similar to that of ALL, with CNS prophylaxis. High-dose chemotherapy with stem cell rescue may salvage some younger patients with aggressive chemotherapy-responsive lymphomas. Prognosis Low-grade (indolent) lymphomas are readily controllable initially, but relapse usually occurs even after many years of remission. Approximately 40% of high-grade lymphomas are cured. 9.6.8 Myeloma In myeloma there is a clonal proliferation of plasma cells and the clinical manifestations of disease are related to substances secreted by the plasma cells as much as to the effects of marrow infiltration. Clonality (all cells of the disease originating from one parent plasma cell) may be confirmed by either of the following: • The presence of paraprotein (monoclonal) band on serum electrophoresis Immunophenotyping the increased numbers of plasma cells in the bone marrow, and • demonstrating that they all express κ or λ light chains rather than a mixture of the two, which would be seen in a normal plasma cell population Imbalance in the ratio of κ to λ light chains in cases where these are secreted into the blood or • urine (see below). The incidence of the different types of myeloma is related to the relative numbers of molecules of the different immunoglobulins in the blood, ie because IgG is present in the highest concentration it is the most common type of myeloma, with IgA next, IgM rare and IgE/IgD very rare. Plasma hyperviscosity syndrome may be found when plasma viscosity exceeds 4 cP (centipoise). This consists of confusion, capillary bleeding, oedema and renal impairment. The incidence of hyperviscosity syndrome relates to the size of the immunoglobulin molecule as well as its concentration. As IgM is the largest immunoglobulin molecule, this syndrome is seen relatively frequently in IgM myeloma, less frequently in IgA myeloma and is rare in IgG myeloma. However, see the comment above about the relative incidence of the different types of myeloma. Red cell transfusion should be avoided if possible in patients with plasma hyperviscosity syndrome, because it will cause a big increase in whole blood viscosity. Investigations used in the diagnosis of myeloma: Investigation Purpose Serum protein electrophoresis Detect the monoclonal immunoglobulin band present in three quarters of cases Immunoglobulin levels Ig levels other than the actual paraprotein class are supressed in myeloma; all are supressed in ‘‘non secretory myeloma’’ Blood count Cytopenias due to marrow infiltration (CRAB – see above) Bone chemistry Hypercalcaemia. In contrast to many other causes of lytic bone disease, alkaline phosphatase is normal in the absence of fractures. Renal function Renal failure due to hypercalcaemia, tubular blockage by light chains, renal amyloid Serum-free light chains Useful when there is no intact paraprotein but other evidence of (SFLC) in selected cases myeloma – see BJP above Urine Bence Jones protein Identifies ‘‘light chain only’’ myeloma – see above BJP is not identified by conventional urine dipstick Skeletal survey to include skull, chest, spine, pelvis, femur and any symptomatic area Looking for lytic lesions/osteopenia; rarely a single isolated plasmacytoma Isotopic bone scans not of value in myeloma due to lack of osteoblastic (as opposed to osteoclastic) activity. MRI better, PET-CT very good but limited availability Bone marrow aspirate and trephine Normally <5% plasma cells, up to 20% in reactive inflammatory conditions, >20% = myeloma However, % plasma cells depends on whether a lytic lesion is hit or missed – further diagnostic confidence from morphological appearance, κ and λ staining to establish clonality (see above) Cryoglobulin: rarely the paraprotein may be a cryoglobulin, so that the protein precipitates from the plasma in the cold. This may be a cause of vasculitis. Do not confuse cryoglobulin with cold • agglutinin – the latter has antibody activity against red cells, causing them to agglutinate in the cold. The antigenic target of cryoglobulin paraprotein is usually unknown Bence Jones protein: sometimes the malignant plasma cells are so defective that they cannot make a complete immunoglobulin molecule and are able to make only light chains. The latter are small enough to be filtered within the glomerulus and to appear in the urine as Bence Jones proteinuria. They may obstruct the renal tubules and contribute to the renal failure that is often found in myeloma (see Chapter 15, Nephrology). Light chains may also precipitate in the tissues • as one type of (AL) amyloid. Measurement of light chains in serum is now commonly available and allows detection and progression monitoring of myeloma not associated with a serum paraprotein, in which the myeloma cells produce only light chains – ‘light chain myeloma’. Even many so-called ‘non-secretory’ myelomas can be found to have an imbalanced ratio of κ and λ light chains in their serum, pointing to a clonal proliferation of plasma cells. Role of cytokines in myeloma Osteoclast-activating factors stimulate the normal osteoclasts to dissolve bone, and lead to bone pain, hypercalcaemia and pathological fractures in myeloma. In other myeloma cases, interleukin-6 (IL-6) may be produced in excess by bone marrow stromal cells infected with human herpes virus 8 (HHV8). Treatment of myeloma Treatment is indicated for patients who have evidence of myeloma-related tissue damage – ‘CRAB’ – any of: hypercalcaemia, renal impairment, anaemia or bone disease. Stem cell transplantation should form part of treatment once a low bulk of disease has been achieved, although many patients will not be suitable for this procedure because of age or co-morbidities. Drugs used in patients likely to be suitable for autologous transplantation include combinations of the following: Thalidomide or its analogue lenalidomide: the mechanism of action of thalidomide includes • • • • anti-angiogenesis, inhibition of tumour necrosis factor secretion and stimulation of interferon production. As its use as a sedative antiemetic in pregnancy resulted in the birth of many children with severe limb defects, there is a strict programme of prescription control to prevent use in patients who might become pregnant. Sideeffects of somnolence, peripheral neuropathy and skin rash can be troublesome. Lenalidomide causes less sedation but more myelosupression Cyclophosphamide Dexamethasone Bortezomid targets the proteasome enzyme complex within the plasma cell, encouraging apoptosis and inhibiting plasma cell adhesion. Peripheral neuropathy and thrombocytopenia are major side-effects. Melphalan (often given with prednisolone) is a proven drug in myeloma, but it kills marrow stem cells, so is not used in patients for whom autologous stem cell recruitment is likely to be required. It is used in high doses as a conditioning regimen for autologous stem cell transplantation, when the stem cells have been safely stored. Bisphosphonates for bone disease and hypercalcaemia A number of bisphosphonates, such as monthly intravenous pamidronate, have an important role in the prevention of pathological fractures and the treatment of myeloma hypercalcaemia. Prognosis in myeloma Almost all patients with myeloma will die of their disease, except for the small minority of young, fit patients who can access allogeneic stem cell transplantation after successful disease bulk reduction. Differentiation of myeloma from MGUS MGUS Low level of paraprotein (<20 g/L for an IgG • paraprotein) Paraprotein level remains stable over a • period of observation (months or years) • Levels of other immunoglobulins are normal No evidence of bone, kidney or marrow • involvement Myeloma • High level of paraprotein • Level rises with continued observation • Other immunoglobulin levels depressed • Clinical evidence of myeloma The median 5-year survival rate is about 40%. The following factors worsen the prognosis: • • • • Elevated β2-microglobulin level Low serum albumin Cytogenetic abnormalities; presence of deletions of 17p, t(4;14), t(14;16) High degree of plasma cell infiltration in marrow • High level of paraprotein • Elevated creatinine • Low presenting haemoglobin and platelet count Monoclonal gammopathy of undetermined significance A common clinical problem is the differentiation between myeloma and a benign monoclonal gammopathy in patients found to have a paraprotein. Of patients with monoclonal gammopathy of undetermined significance (MGUS), 1% will develop myeloma each year. It is probable that most of these patients would eventually develop myeloma but die of other causes before this develops. MGUS does not require treatment but needs regular monitoring of paraprotein level, blood count, renal function and bone chemistry to detect the progression to myeloma. 9.6.9 Monoclonal antibodies in the treatment of haematological diseases Monoclonal antibodies that are directed against various CD antigens on haematopoietic cells are now established in the treatment of a variety of haematological diseases (Table 9.4). In many cases these are being used on a trial basis. Such antibodies may be administered in their native state or after conjugation to cell poisons or radioactive isotopes. 9.6.10 Polycythaemia Polycythaemia is an increase in red cell count, haematocrit and (usually) haemoglobin. Polycythaemia may divided into the following: True polycythaemia: an increase in red cell mass. True polycythaemia may be either primary (polycythaemia rubra vera, myeloproliferative disease) or secondary to other causes • Relative (pseudo-)polycythaemia: a decrease in plasma volume. • Primary true polycythaemia (rubra vera) This is one of the myeloproliferative disorders. There is uncontrolled production of red cells by the bone marrow, even though erythropoietin is switched off. Clinical features: hypertension, splenomegaly, arterial and venous thromboses, pruritis, plethoric features, peptic ulceration, gout Laboratory features: high red count, haemoglobin, haematocrit, whole blood viscosity and urate. The neutrophil count and platelet count are also often increased and this helps distinguish primary polycythaemia from secondary polycythaemia where these are usually normal. Of • primary polycythaemia patients, 90% have a gene mutation, JAK-2, detectable by PCR on blood cells. This test is a useful initial screening test for new cases of polycythaemia because, if positive, it obviates the requirement to perform more complex investigations to discover the cause of a secondary polycythaemia. • Table 9.4 Monoclonal antibodies used in haematology Antibod Disease treated y Antibody specificity Comments Rituxima B-cell non-Hodgkin’s lymphoma, CD20 b autoimmune disorders In routine use Lymphoproliferative disorders. Campath Immunosuppression in stem cell transplantation CD56 In routine use CD33 Coupled to an anthracycline cell poison Gemtuzu Acute myeloid leukaemia mab Complement-mediated thrombotic Eculizum mico-angiopathies (HUS) and Complement C5 ab paroxysmal nocturnal haemoglobinuria Anti-D Prevention of Rhesus D sensitisation in pregnancy Anti-D Expense limits use In trial – unlike donorderived anti-D, no risk of infectious disease transfer Investigation of polycythaemia In addition to clinical history and examination, cases of JAK-2-negative polycythaemia will often require the following: • • • • • Pulse oximetry Abdominal ultrasonography for kidneys, liver and spleen Plasma erythropoietin Renal function tests and urate Vitamin B12 (elevated in the myeloproliferative disease) • Isotopic measurement of red cell mass/plasma volume to confirm true rather than relative polycythaemia. Secondary true polycythaemia This common condition is associated with increased levels of erythropoietin which are produced by either the kidney or ectopic secretion by a tumour. It is often a physiological response to hypoxia. Pathological causes of secondary true polycythaemia are given in Table 9.5. Pharmacological causes are erythropoietin doping, and use of anabolic steroids for bodybuilding and post sex-change. Relative polycythaemia A reduction in circulating plasma volume can be due to pyrexia, diarrhoea, vomiting and diuretic therapy. The blood count abnormalities resolve after rehydration. ‘Stress polycythaemia’ refers to a relative polycythaemia found mainly in middle-aged men who have stressful occupations and a chronically reduced plasma volume of uncertain cause. Treatment of polycythaemia Treatment is indicated for polycythaemia because high blood viscosity leads to increased incidence of thrombosis, hypertension, stroke and atherovascular disease. Table 9.5 Causes of secondary polycythaemia Due to hypoxia Physiological Congenital cyanotic heart disease Respiratory related High-affinity haemoglobinopathies (rare) Adaption to altitude, in neonates eg tetralogy of Fallot, Eisenmenger’s complex COPD, smokinga eg haemoglobin Mb Due to inappropriate erythropoietin production From the kidney From a tumour eg pyonephrosis, renal cysts, renal artery stenosis, after renal transplantationc eg carcinoma of the kidney, hepatoma, giant uterine fibroids, cerebellar haemangioblastoma aInhaled carbon monoxide combines irreversibly with haemoglobin, forming carboxyhaemoglobin, which is then unavailable for oxygen transport. bAn abnormal structure of the globin chains decreases the ability of the haemoglobin to release oxygen to hypoxic tissues (including the kidney), so more erythropoietin is produced. cAll these pathologies result in decreased oxygen delivery to the juxtaglomerular apparatus, by either increasing the pressure within the renal capsule or reducing the blood supply to the whole kidney. COPD, chronic obstructive pulmonary disease. The following are the main treatment options: Venesection to a target haematocrit: the packed cell volume is more closely related to blood viscosity than the haemoglobin. In primary polycythaemia target haematocrit is <50, in secondary polycythaemia <55, but clinical factors such as history of thrombosis need to be taken into account. Repeated venesection may result in iron-deficient red cells with a low haemoglobin • content. Venesection may be conventional (as in normal blood donation) or isovolaemic (with saline replacement). The latter is used in patients with cardiovascular risk factors (eg angina or hypertension) or in those who are taking drugs that may impair physiological response to venesection (angiotensin-converting enzyme [ACE] inhibitors, β blockers) Cytotoxic agents, particularly hyroxycarbamide: this suppresses erythropoiesis and causes a • macrocytosis that is not related to vitamin B12 or folate deficiency. Unlike the alkylating agents (eg busulphan, chlorambucil), it does not appear to be associated with secondary leukaemia • Aspirin and anticoagulants: if the patient has presented with thrombosis. 9.6.11 Thrombocytosis This may be primary (essential) thrombocythaemia or a secondary thrombocytosis. Most cases where the platelet count is over 1000 × 109/L are due to essential thrombocythaemia unless there is a clinically obvious secondary cause. Causes of secondary (reactive) thrombocytosis • • • • • • • Bleeding Infection Trauma Thrombosis Infarction Iron deficiency (even if not due to bleeding) Hyposplenism Primary thrombocythaemia A common problem is the distinction between primary thrombocythaemia and a secondary thrombocytosis. There may be markers of a myeloproliferative disorder (polycythaemia, splenomegaly, basophilia, increased marrow reticulin, cytogenetic abnormality or hyposplenism caused by multiple splenic infarcts). The patient’s previous blood count records may show a normal platelet count before an event such as surgery/infection that triggered a thrombocytosis. Elevated inflammatory markers suggest a reactive cause, whereas these are often normal in essential thrombocythaemia. Measurement of ferritin may confirm iron deficiency, which should be treated before presuming essential thrombocythaemia. Treatment most commonly employs hydroxycarbamide. As this is potentially teratogenic, pregnant patients or those who may become pregnant are treated with interferon. Aspirin and anticoagulants may be required for thrombosis treatment. Table 9.6 Classification of the myelodysplastic syndromes (MDSs) MDSs Special features Refractory anaemia Dysplastic morphological features seen (see text) but difficult to diagnose with certainty in early stages – other cause of anaemia need excluding Refractory anaemia with excess of blasts (RAEB) As above plus increased numbers of blast cells in the marrow (5–20%; normal <5%) Refractory anaemia with excess of blasts in transformation (RAEB-t) As above but 20–30% blasts in marrow – more than this is acute myeloid leukaemia Chronic myelomonocytic leukaemia (do not confuse with the myeloproliferative disorder chronic myeloid leukaemia, which is associated with granulocytosis rather than monocytosis) Monocytosis in blood and marrow Primary acquired sideroblastic anaemia Ring sideroblasts in marrow (see section 9.2.2) 9.6.12 Myelodysplasias (myelodysplastic syndromes) This group of haematological malignancies is being seen with increasing frequency as the mean age of the population rises and screening blood counts are performed more often. As a group (Table 9.6), they hang together less well than other haematological malignancies but they do have the following features in common: • More common in elderly people, but no age is exempt Cytopenias: normocytic or macrocytic anaemia most common, also neutropenia and • thrombocytopenia, or combinations of these Dysplastic changes seen in blood and bone marrow. These include hypogranular neutrophils, • abnormal neutrophil nuclear lobulation and changes in red cell marrow precursors mimicking megaloblastic change Monocytosis: this may be found in all the myelodysplastic disorders but is most marked (>1 × • 109/L) in chronic myelomonocytic leukaemia A preleukaemic condition – about a third of cases will transform into acute myeloid leukaemia. • Increased numbers of blast cells may be found in the marrow heralding this change Cytogentic abnormalities, as seen in AML, may be seen in MDS. A rare variant of MDS with a relatively good prognosis is 5q– syndrome, found mainly in women with a normal or high • platelet count, increased number of dysplastic megakaryocytes in the marrow and deletion of part of the long arm of chromosome 5. This subtype of MDS responds well to thalidomide/lenolidamide therapy Mainstay of treatment for most patients is support: transfusion/erythropoietin for anaemia, • antibiotics for infection, platelet transfusion for bleeding. 9.6.13 Stem cell transplantation Haematopoietic stem cells for transplantation are now routinely obtained from donors by leukopheresis after treatment with G-CSF and/or other cytokines (see below), obviating the requirement for the general anaesthesia needed for marrow harvesting. Stem cell transplants work by using a strong (myeloablative) treatment such as high-dose cyclophosphamide with total body irradiation to wipe out residual malignant disease. In addition, the donor’s transplanted immune system may recognise malignant cells and destroy them – graft-versus-leukaemia (GVL) effect. The downside of GVL is that the donor’s immunity may attack the recipient’s tissues, particularly the liver, skin, intestine and haematopoietic cells, causing graft-versus-host disease (GVHD). In general, the worse the GVHD the better the GVL effect. Peripheral blood stem cells In the rebound after marrow recovery from chemotherapy, stem cells appear in the peripheral blood. They can be made to appear in larger numbers by using growth factors such as G-CSF. Plerixafor binds to the CXCR4 receptor on stem cells, preventing their attachment to bone marrow and increasing the number that can be harvested by leukopheresis on a cell separator and frozen. Peripheral blood stem cells (PBSCs) are further down the differentiation pathway to mature cells than marrow stem cells, so their use is associated with quicker haematological recovery than seen when bone marrow is used. A slight disadvantage is the inadvertent harvesting of more donor T lymphocytes with the PBSCs, theoretically increasing the incidence of GVHD. The types of donor and stem cells used are shown in Table 9.7. The following are conditions in which a stem cell allograft is a useful treatment if a matched sibling is available and the recipient is fit enough for the procedure: Acute myeloid leukaemia: in first or subsequent remission. However, if good prognosis cytogenetics are present (see section 9.6.2) and the patient is in remission after the first course of • chemotherapy, then a stem cell transplantation is not performed. Also, in elderly patients or those with significant co-morbidities, the risks may outweigh the benefits and conventional chemotherapy may be a more prudent course Acute lymphoblastic leukaemia: in second or later remissions, unless adverse prognostic • features (such as age beyond childhood or adverse cytogenetics) are present, in which case bone marrow transplantation should be performed at first remission Chronic myeloid leukaemia: in the first chronic phase, if imatinib or an alternative tyrosine • kinase inhibitor does not induce a major cytogenetic response and a donor is available with a recipient fit enough for the procedure Table 9.7 Types of donor and stem cells used Type Advantages Disadvantages Autologous Donor available! Poor GVL; possibility of residual bone marrow disease being harvested and returned to patient Syngeneic (identical twin) Full-house HLA match – no GVHD Reduced GVL effect HLA-matched sibling Controllable GVHD but some GVL GVHD unpredictable. Only one in four of our siblings will be an HLA match Matched volunteer, unrelated donor Available if no family match and HLA type is not rare GVHD unpredictable but more than HLA-matched sibling GVHD, graft-versus-host disease; GVL, graft-versus-leukaemia. Other indications: stem cell transplantation for thalassaemia major and sickle cell disease • remains controversial • Others: storage diseases, some lymphomas responsive to second-line chemotherapy. 9.7 COAGULATION 9.7.1 The coagulation mechanism and detection of coagulation factor deficiencies A representation of the coagulation cascades is shown in Figure 9.2. These consist of an extrinsic pathway (in which tissue thromboplastin plays an important part, and the physiologically important one), and an intrinsic pathway (intrinsic to the blood itself – what happens when the blood clots away from the body in a test tube). These two pathways share a final common pathway resulting in the production of a fibrin clot. The system can be divided into boxes, each box representing one of the following three basic screening tests of coagulation: Prothrombin time (PT) measures the extrinsic system and final common pathway. The • international normalised (prothrombin) ratio (INR) is derived from the PT and measures the same thing Activated partial thromboplastin time (APTT) measures the intrinsic system and final common • pathway Thrombin time (TT) measures the final part of the final common pathway. It is prolonged by • lack of fibrinogen to convert to fibrin, and by inhibitors of this conversion, including heparin and high levels of fibrin degradation products. Figure 9.2 shows which factors should be assayed after finding a prolonged coagulation time, eg an isolated prolonged APTT should prompt assay of factors XII, XI, IX and VIII. If the clinical picture is suggestive of haemophilia, then starting with factors VIII and IX may save time. Coagulation inhibitors If one of these screening tests of coagulation is significantly prolonged, then it should be repeated using a mixture of 50% normal plasma and 50% patient plasma. If the cause of the prolonged time is factor deficiency, the abnormal time should correct more than halfway back to the control value. If it does not, this suggests the presence of a coagulation inhibitor such as the lupus anticoagulant, antibodies against coagulation factors (eg anti-factor VIII antibodies developing in someone with haemophilia) or heparin. Figure 9.2 Representation of the coagulation cascade 9.7.2 Haemophilias These diseases are characterised by deep muscular haematomas and haemarthroses with prolonged bleeding after trauma or surgery. There is a deficiency of factor VIII (classic haemophilia) or factor IX (Christmas disease). The disease is classified as severe if the factor level is <1% of normal (<1 unit/dL). Inheritance is sex-linked, although a third of cases have no family history and are due to a spontaneous mutation. Carriers may be detected because they have half the amount of coagulation factor measured by a coagulation assay than they have measured by an immunological assay. Also, restriction fragment polymorphisms (RFLPs) can track the affected chromosome. Diagnosis is by prolonged APTT (but normal PT and TT), which corrects with normal plasma. Factor VIII or IX levels are low. The range of treatments is shown in Table 9.8. Complications of treatment include hepatitis, HIV, development of antibodies against the administered coagulation factors and opiate addiction. 9.7.3 Von Willebrand’s disease This is the most common inherited coagulopathy in the UK, with up to 1% of the population having the disorder on unselected testing. Most of these cases are mild. Von Willebrand’s factor (vWF) is coded for on chromosome 12 – hence inheritance is autosomal dominant. It is caused by a quantitative or qualitative deficiency of vWF production. The vWF is made in endothelial cells and forms variablesized polymers in plasma. Table 9.8 Treatment of haemophilia Treatment Rationale Virally inactivated coagulation factor concentrate Should be given early in the course of a bleed, ideally home treatment DDAVP (a synthetic antidiuretic hormone analogue) Releases factor VIII from storage sites in endothelial cells so can temporarily boost blood levels in mild haemophilia A (not effective in Christmas disease) Fibrinolytic inhibitors (eg tranexamic acid) Delay dissolution of fibrin clot; useful for bleeding wounds but avoid in haemarthrosis, muscle haematomas and urinary bleeding as may lead to resolution by local fibrosis Ancillary treatments (part of ‘total haemophilia care’) Physiotherapy, hydrotherapy, immunisation against hepatitis B, dental and orthopaedic advice The vWF acts as a protective carrier for factor VIII in the circulation and is also responsible for gluing the platelets to exposed vascular subendothelium. Hence, the factor VIII level in vWD is often reduced, but not to the very low levels seen in haemophilia A. Also, in contrast to the haemophilias, the disease manifests as a platelet-type bleeding disorder with bruising, superficial purpura, menorrhagia, nosebleeds, and bleeding from cuts and mucous membranes. Diagnosis • • • • Low factor VIIIc (c for ‘clotting’ activity – a functional assay) Low vWFAg (von Willebrand’s factor antigen measured in an immunological assay) Low vWF:RCo (ristocetin cofactor) – a functional assay of vWF Prolonged in vitro bleeding time (PFA100 test). Ristocetin is an antibiotic that clumps platelets in normal plasma but fails to clump them in vWFdeficient plasma, and this is the basis for a functional assay of vF:, the vWF:RCo ratio. The levels of vWF in normal persons vary according to blood group, group O individuals having less, and this needs to be taken into account when interpreting tests. vWD may divided into subtypes depending on whether the deficiency is quantitative (type I) or qualitative (type II) and on the size of vWF multimers present. Treatment is with DDAVP if mild, and with intermediate purity factor VIII concentrates, which also contain vWF, if the bleeding or the disease is more severe. 9.7.4 Disseminated intravascular coagulation This disorder is caused by the release into the circulation of tissue factor released from dying cells and activated leukocytes that promote coagulation. There is massive activation of coagulation factors and platelets, with laying down of fibrin. This fibrin clot is immediately removed because the fibrinolytic system is also put into overdrive, worsening the haemorrhagic tendency. Treatment is to remove the cause, if possible, and transfuse with red cells, platelets, FFP and cryoprecipitate. Features and causes of disseminated intravascular coagulation • Laboratory features of DIC • Prolongation of all coagulation times (prothrombin, APTT and thrombin) Activation of the fibrinolytic system leading to low fibrinogen and high levels of fibrin • degradation products • Consumption thrombocytopenia • Obstetric causes • Retroplacental haemorrhage • Retained dead fetus • Amniotic fluid embolus • Severe pre-eclampsia • Other causes • Crush injury Septicaemia, particularly with Gramnegative and some Gram-positive including toxin• producing Staph. aureus and Clostridia • Haemolytic blood transfusion reaction • Malignancy, particularly associated with necrosis of tumour cells 9.7.5 Vitamin K-dependent coagulation factors (II, VII, IX and X) Vitamin K is a fat-soluble vitamin essential for the carboxylation of inactive coagulation factors into their active functional form. These coagulation factors are manufactured in the liver, so levels are low in liver disease, obstructive jaundice and when there is fat malabsorption (loss of vitamin K). Levels are also low in the neonate due to liver immaturity – this can lead to haemorrhagic disease of the newborn (not haemolytic disease!), particularly when breastfed. These coagulation factors are also reduced by warfarin anticoagulation. Deficiency causes a prolonged PT and APTT. 9.7.6 Thrombocytopenia There is overcapacity in haemostasis, including the platelet count (Table 9.9) (this assumes normal platelet function). Young platelets tend to be relatively large and efficient compared with old platelets. Hence bleeding at a given platelet count is more severe in underproduction thrombocytopenia than in peripheral destruction thrombocytopenia. In the latter the bone marrow produces more young platelets and if the platelet count is <50 × 109/L, an elevated reticulated platelet count is a useful marker of peripheral destruction, diminishing the need to examine the number of megakaryocytes in the marrow. When thrombocytopenia is associated with other blood count abnormalities, there is a wide differential diagnosis, including most of the haematological malignancies described in Section 9.6. When it is associated with abnormalities of coagulation, the differential diagnosis includes DIC (see section 9.7.4). Isolated thrombocytopenia is usually the result of increased platelet destruction. Causes of isolated thrombocytopenia • • • • • Artefactual: clot in the sample or platelet clumping. This can be confirmed by examination of the sample and the blood film. When platelets are clumped, sometimes a more accurate count can be obtained by using citrateor heparin-anticoagulated blood sample tubes, or performing an ‘instant’ blood count on a blood counter located close to the patient Idiopathic or immune thrombocytopenia: very common – see below Drugs: heparin, abciximab, quinine, valproate, sulfonamides, dopa, interferons Hypersplenism: the spleen contains about a third of the circulating platelets, and if the spleen is enlarged from any cause this may be associated with thrombocytopenia (see Section 9.9.1 for the causes of splenomegaly) Gestational thrombocytopenia: the platelet count is usually >70 × 109/L, and the patient is clinically well with no symptoms of preeclampsia or abnormality of liver function. HELLP syndrome (haemolysis with elevated liver enzymes and low platelet count) manifests as haemolytic anaemia with liver function abnormality and thrombocytopenia, is associated with pre-eclampsia and should be included in the differential diagnosis. Table 9.9 Clinical risks of different degrees of thrombocytopenia Platelet count × 109/L Clinical effect 140 100 50 20 <10 Lower limit of normal range Normal haemostasis, including surgery Normal haemostasis unless challenged Minor risk of bleeding Significant risk of bleeding Immune thrombocytopenia This is the most common cause of an isolated thrombocytopenia and is an autoimmune disease. However, obtaining sufficient platelets to prove this is difficult in the context of thrombocytopenia, so a diagnosis immune thrombocytopenia (ITP) is often made by the absence of other causes of thrombocytopenia. When the platelet count is >100 × 109/L, without evidence of other disease, it is reasonable not to perform marrow examination but to observe the platelet count at follow-up, (with decreasing frequency if it is stable). The following medical disorders are associated with ITP and need to be excluded: • • • • • SLE autoimmune haemolytic anaemia (with ITP is Evans’ syndrome) viral infection: HIV, Epstein–Barr virus (EBV), hepatitis C antiphospholipid syndrome (Hughes’ syndrome) Helicobacter gastritis. When the platelet count is <20 × 109/L or associated with significant bleeding, treatment is indicated and it is usual to examine the bone marrow to confirm normal or increased numbers of megakaryocytes. Sometimes, however, the immune reaction is directed against megakaryocytes, so marrow examination is important for excluding other haematological diseases as the cause of thrombocytopenia. Initial treatment is usually with prednisolone 1 mg/kg per day. The dose may be reduced to decrease side-effects when the platelet count is haemostatic (>20 × 109/L). Gastroprotection in the form of an H2-receptor antagonist is usual and aspirin/NSAIDs should obviously be avoided. Sometimes steroids need to be continued for up to 3 months for maximum effect. The addition of azathioprine may have a useful steroid-sparing action. For steroid-resistant cases, other treatments are as follows: • • • • Splenectomy: about two-thirds of patients benefit from splenectomy, because either this enables discontinuation of steroid or lower doses are then required to achieve a haemostatic platelet count (see section 9.9 for post-splenectomy precautions) High-dose intravenous immunoglobulin will improve the platelet count in a few days, but its effects are often short-lived; it is indicated before surgery and for emergency treatment Intravenous anti-D: applicable to only the 80% of patients who are Rhesus D positive. The administered anti-D coats their red cells, which are preferentially destroyed by the spleen and reticuloendothelial system, sparing the platelets. A drop of 10–20 g/L in the haemoglobin level is to be anticipated, and note that anti-D seems to be ineffective in splenectomised patients Rituximab: this anti-CD20 antibody has an emerging role in the treatment of refractory cases. 9.8 THROMBOSIS There are many well-recognised risk factors for venous thromboembolism and in these situations it may be appropriate to take prophylactic measures. General clinical risk factors for venous thrombosis • Previous thrombosis • Increasing age • Immobility • • • • • • • • • • • • • • Obesity Major abdominal and hip operations Oestrogen/contraceptive pill After a myocardial infarction or stroke Nephrotic syndrome Smoking Varicose veins Family history of thrombosis Cancer Trauma/surgery on the lower limbs Pregnancy and the puerperium Diabetic hyperosmolar state Paroxysmal nocturnal haemoglobinuria Thrombophilia (see Section 9.8.3) Therapeutic INR ranges for warfarin anticoagulation The necessary degree of anticoagulation will vary depending on the indication (Table 9.10) and whether the causes (eg bed rest, fracture) can be removed. Table 9.10 Therapeutic INR ranges for warfarin anticoagulation Indication INR range Atrial fibrillation, treatment of DVT/PE, systemic embolism, post-MI, transient 2.0–3.0 ischaemic attacks Recurrent DVT/PE, arterial disease including MI, mechanical prosthetic valves 3.0–4.5 DVT, deep vein thrombosis; INR, international normalised ratio; MI, myocardial infarction; PE, pulmonary embolism. 9.8.1 Venous thrombo-embolism (VTE) prophylaxis In 2005 it was estimated that 25,000 patients per annum suffered hospital acquired VTE. All adults admitted to hospital should have VTE risk assessment on admission. Risk factors for VTE in medical patients • • • • Critical care admission Age >60 years Likely reduced mobility for 3 days or more Obesity BMI >30 kg/m2 • Congenital or acquired thrombophilia (see below) • Oestrogen/contraceptive pill • After a myocardial infarction or stroke Significant medical illness – eg nephrotic syndrome, heart failure, myocardial infarction, • diabetic hyperosmolar state • Cancer diagnosis • Varicose veins with phlebitis, or history of VTE • pregnancy and the puerperium Such patients should be offered pharmacological VTE prophylaxis, most commonly with daily subcutaneous LMW heparin (see above) or fondaparinux, unless risk factors for bleeding are present (see below). Risk factors for bleeding with anticoagulant prophylaxis in medical patients • • • • • Congenital or acquired bleeding disorder eg von Willebrand disease, synthetic liver disease Lumbar puncture due within 12 hours, or performed less than 4 hours ago Acute stroke Thrombocytopenia, platelets <75 × 109/L Uncontrolled hypertension Non-pharmacological VTE prevention measures, applicable to all patients, include encouraging mobilisation, avoiding dehydration and physical methods to increase venous return from the legs eg antiembolism stockings, calf compression devices. A full consideration of hospital VTE prophylaxis can be found on the NICE website, or in local hospital guidelines. 9.8.2 Thrombosis and the pill Administration of oestrogen-containing pills: • Increases fibrinogen and vitamin K-dependent clotting factors • Decreases antithrombin levels • Gives a four times greater risk of thromboembolism. The risk of thromboembolism is increased by eight times if factor V Leiden is present; it is important to screen all women with a history of thrombosis if starting on the combined oral contraceptive pill. Hormone replacement therapy is also associated with a small risk of thrombosis and women with a history of thromboembolism should be screened for thrombophilia. 9.8.3 Thrombophilia Congenital thrombophilia The blood contains clotting factors that promote the formation of thrombus when activated. This system is in balance with a group of natural anticoagulants that inhibit clot formation: • Antithrombin: the most common inherited natural anticoagulant deficiency • Protein C: vitamin K-dependent natural anticoagulant • Protein S. A congenital deficiency of these factors results in a tendency to thrombosis, so they are measured when testing for inherited thrombophilias Normally, activated factor V is inactivated by the anticoagulant protein C. Approximately 3–5% of Europeans have an abnormal structure to their factor V, caused by a single point mutation in the factor V gene. This means that protein cannot bind to and inactivate it. This abnormal factor V is called factor V Leiden after its place of discovery; it is found in 30% of patients with recurrent thrombosis. Screening for factor V Leiden may be done by PCR on blood. The following are other causes of inherited thrombophilia: • Prothrombin gene mutation: similar to factor V Leiden, can be detected by PCR • Dysfibrinogenaemia • Fibrinolytic defects. Acquired thrombophilias • Polycythaemia and essential thrombocythaemia • Lupus anticoagulant/antiphospholipid antibodies. Antiphospholipid antibodies include lupus anticoagulant, anticardiopin antibodies and anti-beta 2 glycoprotein 1 antibodies. They have a strong association with each other and with immune thrombocytopenia. Paradoxically, lupus anticoagulant, causing venous thrombosis, is detected by a prolonged coagulation test such as the APTT, or the more sensitive DRVVT (dilute Russell viper venom time). The coagulation times are prolonged because antiphospholipid antibodies neutralise phospholipids that are essential for the coagulation reaction. Although it may be found in patients with SLE, most patients with lupus anticoagulant do not have SLE. The disorder may present with recurrent venous thromboembolism or recurrent miscarriages. (See also Chapter 12, Maternal Medicine.) Strict criteria for the diagnosis of lupus anticoagulant require confirmation by a repeat test 12 weeks after the first (some lupus anticoagulants are a temporary phenomenon associated with intercurrent illness). The prolonged DRVVT should fail to correct with the addition of normal plasma, but should correct when an excess of phospholipid is added to the plasma. 9.8.4 Therapeutic fibrinolysis Therapeutic fibrinolysis • Action • Conversion of plasminogen to plasmin which dissolves fibrin to fibrin degradation products • Indications Early stages of myocardial infarction, young patients with proximal deep venous thrombosis • eg iliofemoral, survivors of massive pulmonary embolism, peripheral arterial thrombosis • Drugs Sreptokinase, urokinase, tissue plasminogen activator (tPA), anisoylated plasminogen • streptokinase activator (APSAC) • Unwanted effects • Bleeding • Reversal • Administration of tranexamic acid, cryoprecipitate 9.8.5 Low-molecular-weight heparin Conventional heparin is a mixture of different-sized polymers. Low-molecular-weight fractions can be separated by various chemical and physical methods. Low-molecular-weight heparin (LMWH) has a molecular weight of 5000 Da, compared with average 15 000 Da for unfractionated heparin. LMWH has strong anti-factor Xa and relatively weak antithrombin action compared with conventional heparin. It is claimed that this gives it more antithrombotic effect with less risk of bleeding. It certainly means that no significant prolongation of the APTT is found, so this test is not used for monitoring therapy. Measurement of its anti-factor Xa effect is possible, although this is necessary only if prolonged treatment is required. Advantages of LMWH • Long half-life – once or at most twice daily administration • Laboratory assays are not required for short-term administration • Less heparin-induced thrombocytopenia and osteopenia than conventional heparin. Disadvantages of LMWH • No easy antidote for reversal in the event of bleeding • Expensive, but allows outpatient-based antithrombotic therapy • Different doses for different brands When given for more than a few weeks (eg in pregnancy) requires (relatively) complicated anti• factor Xa assay for monitoring. 9.8.6 Direct-acting oral anticoagulants Unlike warfarin, which works through the inhibition of hepatic synthesis of active coagulation factors, these new oral anticoagulants directly inhibit coagulation factors, eg dabigatran inhibits thrombin, rivaroxaban and apixaban inhibit Xa. Advantages in comparison to warfarin • Rapid action, peak concentration in circa 3 hours • Rapid elimination in circa 12 hours • Much fewer drug and food interactions No requirement for coagulation test monitoring. Although the Xa inhibitors prolong the prothrombin time, and thrombin inhibitors prolong the thrombin time and APTT, the relationship • between clotting time and clinical effect/bleeding risk is too approximate and assay-dependent for routine use. For dabigatran, measuring drug level may reduce bleeding episodes in the elderly Efficacy equivalent or superior to warfarin; in the context of AF, less intracerebral bleeding but • more GI bleeds with higher dose of dabigatran. Disadvantages in comparison to warfarin • Expensive – usually restricted to warfarin failures in NHS practice No universally accepted antidote in the event of bleeding – but levels drop in hours and • prothrombin complex concentrate has been used • Dose adjustment required in renal failure Shorter half life results in rapid decline in anticoagulation if doses are missed and requires • multiple daily dosing. 9.9 THE SPLEEN 9.9.1 Causes of spenomegaly • Myeloproliferative disorders • Myelofibrosis • Chronic myeloid leukaemia • Primary polycythaemia • Essential thrombocythaemia (splenic atrophy also common) • Portal hypertension • Cirrhosis • Congestive cardiac failure • Bacterial infections • Typhoid, brucella, TB, subacute bacterial endocarditis • Viral infections • Glandular fever, hepatitis • Collagen diseases • Chronic haemolytic anaemias • Warm autoimmune haemolytic anaemia • Cold haemagglutinin disease • Lymphoproliferative disorders • Most lymphomas • Chronic lymphocytic leukaemia • Hairy cell leukaemia • Tropical • For example, malaria, kala-azar • Storage diseases 9.9.2 Splenectomy Often performed because of traumatic injury or haematological disease, this operation results in a characteristic blood film appearance and a well-recognised predisposition to sudden overwhelming infection with capsulated organisms such as Pneumococcus or Haemophilus spp. Clinical indications for splenectomy • • • • Traumatic rupture: although surgeons may preserve splenic function by surgical repair of capsular tears, omental patches and sometimes implantation of some splenic tissue in the retroperitoneum Autoimmune destruction of blood cells: immune thrombocytopenia and warm autoimmune haemolytic anaemia after failure of steroid therapy Haematological malignancies: low-grade lymphoproliferative disorders associated with painful splenomegaly, hypersplenism and not much disease outside the spleen. Also sometimes performed in the myeloproliferative disorders, particularly in myelofibrosis when an enlarged or painful spleen is destroying more blood cells than it is producing Congenital haemolytic anaemias: particularly the red cell membrane disorders such as spherocytosis and elliptocytosis and some cases of hypersplenism in β-thalassaemia major. Haematological and immune changes after splenectomy Howell–Jolly bodies: nuclear remnants in the red cells – the spleen is responsible for removing particulate material from red cell cytoplasm – pitting function • Enhanced neutrophilia in response to infection Target cells, thrombocytosis, occasional spherocytes and increased red cell aniso- and • poikilocytosis • • Decreased IgM levels • Mild polyclonal T-cell lymphocytosis. 9.9.3 Causes of hyposplenism • Splenectomy (see Section 9.9.2) • Sickle cell disease • Coeliac disease Myeloproliferative diseases associated with splenic infarcts, particularly essential • thrombocythaemia • Congenital asplenism (rare) Infection prophylaxis in hyposplenic patients • Pneumococcal vaccine • Haemophilus influenzae vaccine (Hib) • Meningitis C vaccine Prophylactic lifelong oral phenoxymethylpenicillin twice daily (or erythromycin if patient is • penicillin-allergic) • Meticulous anti-malarial prophylaxis, including insect repellant and mosquito net • A warning card for the patient to carry is available from the Department of Health. The above applies to hyposplenic patients as well as previously splenectomised patients recognised by the film comment ‘Howell–Jolly bodies’ on routine blood count. If penicillin prophylaxis is declined, then they should keep a supply of amoxicillin at home to take at the first sign of infection. 9.10 BLOOD TRANSFUSION 9.10.1 Better blood transfusion The British government’s ‘Better blood transfusion’ initiatives have promoted the importance of reduced blood product consumption in several ways: Routine pre-admission assessment including blood count and preoperative correction of haematinic deficiencies before elective surgery Establishment of maximum blood order schedules (MBOS) with agreed quantities of crossmatched blood being provided for specified operations. In general, if the chance of blood being • needed for an elective operation is <30%, then only a ‘group and screen’ need be performed. If the screen for atypical red cell antibodies is negative, then there should be no problem obtaining compatible blood in an emergency Increased use of ‘group and screen’ with accelerated compatibility testing rather than the issuing • of cross-matched blood for operations • Adoption of lower haemoglobin thresholds for post-operative transfusion. There is usually no indication for red cell transfusion if the haemoglobin is >100 g/L. Transfusion is usually given if • the haemoglobin is <70 g/L, in otherwise fit patients, or Hb <90 g/L in patients with cardiovascular disease or aged >70 years • Intraoperative and post-operative red cell salvage is encouraged Use of erythropoietin in diseases associated with anaemia such as myelodysplasia, myeloma, myelofibrosis and advanced chronic kidney disease. Measurement of serum erythropoietin level • may provide a guide to likely response – <100 IU/L likely to respond, >500 unlikely to respond, 100–500 discuss a trial of erythropoietin. 9.10.2 Transfusion-transmitted infection Periodically, transfusion-transmitted infections hit the headlines, resulting in patients’ reluctance to accept blood products. The infection of most concern was variant Creuzfeldt–Jakob disease (vCJD) or ‘mad cow’ disease, the prion protein of which is not destroyed by conventional heat-detergent viral inactivation procedures. A screening test for carriers of this disease is being developed, although it is feared that introduction of such a test may shrink the donor pool, because potential donors may not wish to have a test for a disease for which no treatment is currently available. All cellular blood products issued by the UK blood service are leukodepleted at source. Leukodepletion by filtration has the following advantages: • Reduced possibility of vCJD transmission • Reduced incidence of non-haemolytic febrile transfusion reactions Decreased transmission of cytomegalovirus (CMV) to CMV-negative blood transfusion • recipients Reduced incidence of third-party GVHD, which is usually fatal and caused by the transfusion of • immunocompetent lymphocytes to immunodeficient recipients. Testing donations for transfusion-transmitted infection in the UK • • • • • • HIV antibodies: there remains a very small risk of viral transmission from infected donors, when they donate in the 8-week window after HIV infection and before antibody production Hepatitis B surface antigen Hepatitis C nucleic acid (antigen) Syphilis screen Human T-lymphotrophic virus (HTLV) antibody CMV antibody (some donations only) to ensure enough CMV-negative products for transfusion to premature neonates and immunosuppressed patients who would be at risk of transfusiontransmitted CMV. 9.10.3 Platelet transfusion in marrow failure Platelet transfusion is usually administered when the platelet count is <10 × 109/L in cases of thrombocytopenia due to marrow failure after chemotherapy or radiotherapy. The platelet transfusion threshold may be reduced as a result of clinical criteria such as bleeding, fever, splenomegaly or planned surgical procedures. • • • • Platelet transfusions should not be used in conditions with peripheral platelet destruction (eg immune thrombocytopenia), except in cases of haemorrhagic emergency. Efforts should be directed at reducing platelet destruction with immunosuppression Platelet transfusion is contraindicated in TTP and HUS because it will contribute to the microvascular occlusion in the brain and kidneys that is associated with these conditions Platelet concentrates are obtained by the thrombocytopheresis of donors who have a high platelet count on the cell separator. One adult dose of platelets contains more than 2 × 1011 platelets Less commonly, the unit of platelets is prepared by pooling the platelets extracted from 4–6 units of fresh blood. Platelet refractoriness is defined as an increment of platelet count <20 × 109/L 1 hour after transfusion of an adult dose. This may be due to the following: • Non-immune consumption (eg bleeding, DIC, hypersplenism) Immune consumption due to HLA antibodies directed against class I HLA antigens present on • platelets (90% of cases). Give HLA-matched, cell-separated platelets and consider plateletpheresis of relatives • Immune platelet-specific antibodies (10% of cases): use double doses of random platelets. 9.10.4 Indications for the transfusion of fresh frozen plasma • Correction of multiple coagulation factor deficits as in DIC or after massive transfusion Correction of single coagulation factor deficiency where a virus-inactivated concentrate is not • available Emergency correction of warfarin over-anticoagulation where prothrombin complex concentrate • is not available and intravenous vitamin K would be too slow (a few hours) • Treatment of TTP or HUS with or without large-volume plasma exchange. The formula replacement of coagulation factors by FFP after large-volume blood transfusion is no longer recommended – it is better to perform a coagulation screen, and give FFP as required. Chapter 10 Immunology CONTENTS 10.1 Introduction 10.1.1 An overview 10.1.2 Innate immunity 10.1.3 Adaptive immunity 10.2 Complement 10.2.1 Hereditary angioedema 10.3 Cells of the innate immune system 10.4 Cytokines and chemokines 10.5 Cells of the adaptive immune system 10.5.1 B cells and antibodies 10.5.2 T cells 10.6 Hypersensitivity 10.6.1 Latent tuberculosis screening 10.7 Transplantation 10.8 Immunodeficiency 10.8.1 Patterns of infection in immunodeficiency 10.9 Immunisation 10.9.1 Principles of immunisation Immunology 10.1 INTRODUCTION The immune system must be credited as one of the most remarkable feats of engineering in the human body. The ability to provide a robust defence against the enormous array of pathogens to which we are exposed during our lifespan, combined with a reassuringly low incidence of serious mistakes, represents a truly phenomenal achievement. What makes immunology particularly fascinating is that, in recent years, there has been a vast increase in our understanding not only of immunity but also our ability to manipulate it to our advantage in clinical practice. In fact, one might argue that we have learnt to run before we can walk in respect to this latter point! 10.1.1 An overview The primary function of the immune system is to provide host defence against invading pathogens. The system can be broken down into two key components: • Innate immunity • Adaptive immunity. The innate immune system (including antigen-presenting cells, eg dendritic cells) is typified by a rapid response to pathogens, but this response is not specific and lacks any ‘memory’. The adaptive system (including B and T cells) takes longer to respond; however, responses are highly specific and a lasting memory exists. Although these two systems are described in more detail in this chapter, it is important to remember that the different components of the immune system do not function in isolation – but rather act in concert, with a vast array of communication networks (comprising chemokines and cytokines) enabling crosstalk between the different cells. Figure 10.1 highlights some of the key cellular components of the immune system. Figure 10.1 The cells of the innate and adaptive immune systems 10.1.2 Innate immunity The innate immune system is the first line of defence against infection. The most obvious example of a component of the innate immune system is the skin; however, at a cellular level this includes monocytes, neutrophils, mast cells and complement proteins. The innate immune response is not specific and lacks any memory. Phagocytic cells located at sites of invasion (typically a resident macrophage) use pattern-recognition receptors (eg toll-like receptors) to identify antigenic motifs referred to as pathogen-associated molecular patterns (PAMPs). Recognition of a PAMP will trigger a series of steps: • Complement activation (to kill invading pathogens) • Chemokine release (increase adhesion molecule expression) • Cytokine release (recruit adaptive immune cells). After phagocytosis of a pathogen, antigen-presenting cells (APCs) can then express the pathogenic peptides on their cell surface for recognition by adaptive immune cells. 10.1.3 Adaptive immunity The adaptive immune system is found only in vertebrate organisms, and provides a highly specific response to invading infection. In humans, the adaptive immune system subdivides into cellular and humoral systems. The hallmarks of the adaptive immune response are specificity and memory. The humoral system refers to the ‘circulating’ immunity: B cells produce antibody that can recognise specific pathogens; however, these pathogens must be visible in the circulating fluids (blood, lymph) of the body. Once the humoral immune system has encountered a pathogen, it is able to produce memory cells that would be able to mount a more rapid and effective response should that pathogen ever be encountered again (Figure 10.2). Many pathogens evade the humoral immune system by residing inside cells (eg viruses). In order to recognise intracellular pathogens, a ‘cellular’ immune system has evolved. Almost all cells are able to express samples of their intracellular contents on their cell surface using machinery referred to as the human leukocyte antigen (HLA) presentation system (encoded on chromosome 6 in the major histocompatibility complex [MHC] region). Most cells express class I HLA, which can be thought of as a form of housekeeping; a small number of ‘professional’ APCs express class II HLA: these are the cells of the innate immune system that spend their days phagocytosing extracellular material for the purpose of antigen expression. The cellular immune system (T cells) can then interact with HLA to determine whether the peptides expressed are self or non-self. Figure 10.2 Memory with the adaptive immune system HLA • • • • Coded for on the short arm of chromosome 6 Class I expression (recognised by CD8 T cells) on most cells Except red blood cells (RBCs) and trophoblasts Class II expression (recognised by CD4 T cells) on ‘professional’ APCs 10.2 COMPLEMENT This is a plasma protein cascade (akin to the clotting cascade) that, once triggered, leads to the formation of the membrane attack complex (MAC). The MAC is one of the key mechanisms by which the immune system can destroy an invading entity, by creating a pore in the cell membrane. Exposure of the highly osmolar intracellular milieu to the extracellular fluid leads to rapid influx of fluid and ultimately osmotic cell lysis. Complement can be activated by one of three distinct pathways: 1. Classic 2. Alternative 3. Lectin-binding. Each pathway produces protein complexes capable of cleaving the C3 component into its active metabolites, C3a and C3b, which in turn activate the terminal complement components (C5–9) which join to form a rosette-like structure: the MAC. This structure forms on cell surfaces and will cause cell lysis unless specific inhibitors are present. These inhibitors are generally ubiquitously expressed, except in disease states, such as in paroxysmal nocturnal haemoglobinuria. Here, the absence of a red cell complement inhibitor as a result of a genetic mutation, is the cause of uncontrolled RBC lysis. Complement pathways are activated during infection (bacterial, viral, fungal) and it is unlikely that any particular pathway is predominant. The classic pathway is thought to be the most recently evolved, and is the only pathway to require antibodies for activation. The alternative and lectinbinding pathways can activate MAC in the absence of antibody by binding directly to polysaccharide components of cell walls of bacteria and yeasts. The complement cascade slowly ticks over and is never completely inactive. This produces small quantities of active complement components. Positive feedback loops would be triggered and cause immune complex activation if it were not for important regulatory components (eg C1q deficiency predisposes to the development of systemic lupus erythematosus [SLE] – the archetypal immune complex disease). The biologically active complement products have three main effects: 1. Opsonisation 2. Chemotaxis and inflammation 3. Cell lysis (MAC). In clinical practice, measurement of components C3 and C4 are used to detect diseases in which complement activation is occurring. Depletion of C3 and C4 would suggest an immunologically driven disease. Typical examples of diseases associated with hypocomplementaemia for the MRCP include the following: • SLE • Mesangiocapillary glomerulonephritis • Chronic infections (eg endocarditis, quartan malaria). Complement • The classic pathway is activated by antibody • Inherited C1q deficiency is a risk factor for SLE Deficiency of the glycophosphatidylinositol anchor results in a failure of red cells to inhibit • complement lysis: this is the pathogenesis of paroxysmal nocturnal haemoglobinuria • The alternative pathway can be activated directly by pathogen-associated molecular patterns • The final common pathway involves C5–9 forming an MAC, resulting in osmotic cell lysis • Final common pathway deficiencies result in recurrent Neisseria spp. infections 10.2.1 Hereditary angioedema Figure 10.3 Angioedema on the tongue This is an autosomal dominant disease caused by a mutation in the C1 inhibitor gene. The role of C1 inhibitor is as a regulator of the classic complement pathway (Figure 10.4), and also an inhibitor of kallikrein, which in turn can liberate bradykinin. Figure 10.4 The complement cascade Deficiency of C1 inhibitor results in recurrent attacks of bradykinin-driven angioedema. These episodes are distinguishable from anaphylaxis because hereditary angioedema attacks do not cause urticaria or hypotension. 10.3 CELLS OF THE INNATE IMMUNE SYSTEM The innate immune system cells are primarily those of myeloid lineage (with the exception of some natural killer cells): Neutrophils – polymorphonuclear cells (PMNs) are the principal cells that are able to engulf and • then directly kill invading microorganisms through the production of intracellular reactive oxygen species using NADPH oxidase Macrophages – they begin their life as monocytes. Upon exiting the lymphatic circulation into • tissues, monocytes differentiate into macrophages. Alongside dendritic cells, these represent one of the ‘professional’ APCs Natural killer (NK) cells – these are lymphoid lineage cells that are able to recognise virally infected cells. NK cells also play a role in tumour surveillance. They share some features in • common with both innate and adaptive immune systems (hence their inclusion in the overlap in Figure 10.1) Eosinophils – these are granular cells that are important in allergy and defence against parasite • invasion. You may notice that basophils have not been mentioned in this list. For MRCP purposes, it is perhaps worth mentioning that you are very unlikely to ever encounter an isolated basophilia outside the setting of a leukaemic process (usually chronic myeloid leukaemia or CML). 10.4 CYTOKINES AND CHEMOKINES Cytokines and chemokines are signalling proteins that enable crosstalk between the components of the immune system, and drive cellular movement and action. There are vast numbers of these proteins; however, for the purpose of the MRCP it is useful to consider only the clinically relevant ones (Table 10.1). Table 10.1 Key cytokines and their clinical relevance Name Function MRCP relevance Proinflammatory produced by innate immune cells Upregulated in many ‘autoinflammatory’ diseases, eg periodic fever syndromes. Can be blocked by anakinra (which can be an effective treatment for periodic fever syndromes) IL-2 Drives T-cell proliferation IL-2 inhibition is clinically useful for suppressing T-cell-driven disease, eg transplant rejection. Examples include the calcineurin inhibitors ciclosporin and tacrolimus IL-6 IL-6 inhibition (eg tocilizumab) is a Proinflammatory cytokine that is key driver treatment for rheumatoid arthritis. Patients of acute-phase response (especially CRP on this therapy are unable to mount a CRP production) response during infection (and so a normal CRP would not be reassuring in this setting) IL-10 Anti-inflammatory cytokine: downregulates Not much really – but one of the few truly other cytokine production, suppresses HLA ‘anti-inflammatory’ cytokines class II expression IL-1 Th17 cells are a recent discovery and manipulation of this proinflammatory pathway is likely to become very important in the coming years IL-17 Stimulates production of Th17 cells TNF TNF inhibition (eg adalimumab) has Proinflammatory cytokine produced become a mainstay of therapy in rheumatoid primarily by macrophages to recruit T cells. arthritis. Side-effects include reactivation of Central to granuloma formation granulomatous disease (ie tuberculosis). IFN Proinflammatory cytokine important in response to viral infections IFNs are administered clinically as a treatment for chronic viral infections (hepatitis C) and also multiple sclerosis. Most common side-effects are flu-like symptoms CRP, C-reactive protein; IFN, interferon; IL, interleukin; TNF, tumour necrosis factor. 10.5 CELLS OF THE ADAPTIVE IMMUNE SYSTEM When considering the cells of the adaptive immune system, think of lymphocytes. 10.5.1 B cells and antibodies B cells develop and mature in the bone marrow. Their name derives from their original discovery in the bursa of Fabricius in birds, despite the fallacious etymology that is often taught in medical schools. During the maturation phases, B cells are important APCs. As they mature they also begin to express immunoglobulin. The terminally differentiated B cell is the plasma cell, which is able to secrete immunoglobulin (antibody). Antibodies (or immunoglobulins) are large glycoproteins that can identify and neutralise pathogens. Antibodies comprise two basic structural units: a pair of large heavy chains and a pair of small light chains. At the very tip of the antibody structure is the ‘hypervariable region’. This is the section that determines to which unique antigen the antibody will bind. Antibodies are grouped into isotypes depending on the heavy chain that they possess. These isotypes and their function are listed in Table 10.2. Antibodies can vary isotype in a process called ‘class switching’ which changes the base of the heavy chain to another. Cryoglobulins These are immunoglobulins that precipitate out upon exposure to cold temperatures. Cryoglubulinaemia can be subdivided into three types, depending on whether the cryoprecipitate is monoclonal, polyclonal or a combination: Table 10.2 Antibody isotypes Antibody Structure Function MRCP notes IgG Monomeric Most abundant Ig (>75%), responsible for most antibodybased responses to infection. Four subclasses: IgG1–4 IgG is the only antibody to cross the placenta. Deficiency predisposes to recurrent bacterial infection IgM Pentameric First antibody isotype to respond to a new infection Useful in serodiagnosis: IgM confirms recent infection Monomeric Binds allergens, triggers mast cell degranulation, provides defence against parasite infections Involved in type I hypersensitivity reactions (including anaphylaxis). A monoclonal antibody (omalizumab) against IgE is NICE-approved for use in severe allergic asthma Dimeric Important in host defence in IgA deficiency is associated mucosal tissues, eg respiratory with autoimmune disease (eg tract and gut coeliac disease) Monomeric A puzzle. If you find out, a Nature paper awaits you IgE IgA IgD Hyper-IgD syndrome is a rare autosomal recessive periodic fever syndrome NICE, National Institute for Health and Care Excellence. Types of cryoglobulins Type 1: monoclonal IgM cryoglobulin: seen in Waldenström’s macroglobulinaemia; clinical features primarily related to hyperviscosity • Type 2: mixed monoclonal/polyclonal cryoglobulin: seen in chronic infections, eg hepatitis C • Type 3: polyclonal cryoglobulin: seen in connective tissue diseases, eg Sjögren syndrome/SLE • Patients with type 2 and 3 cryoglobulinaemias may present clinically with vasculitis (palpable purpura, renal failure, arthritis). It is common to see a positive rheumatoid factor in these patients. Cold agglutinin disease This should not be confused with cryoglobulinaemia. Cold agglutinin disease is a form of haemolytic anaemia. It can be either idiopathic or acquired. For the MRCP, the two most important acquired causes are lymphoproliferative disease and Mycoplasma pneumoniae infection. Rituximab Rituximab is a chimseric monoclonal antibody that causes complement-mediated lysis of cells expressing the CD20 antigen – which is present on immature, mature and some memory B cells. Rituximab does not deplete haematopoietic stem cells nor does it destroy plasma cells or immunoglobulin. Rituximab was first developed as a targeted therapy for diffuse large B-cell lymphoma (in combination with CHOP – cyclophosphamide, Adriamycin [hydroxydaunorubicin], vincristine [Oncovin] and prednisolone) – but has subsequently been found to be efficacious in the treatment of rheumatoid arthritis, systemic vasculitis, idiopathic thrombocytopenic purpura (ITP) and other autoimmune diseases. It is currently in trials for the prevention of type 1 diabetes mellitus. Congratulations to anyone who foresaw this success in 1996 and bought shares when it was first licensed. 10.5.2 T cells T cells make up around two-thirds of the circulating lymphocyte population. Similar to the B cell they are manufactured in the bone marrow; however, maturation takes place in the thymus gland. During the maturation phase, autoreactive cells are removed and then develop into either T-helper (recognising class II HLA) or cytotoxic (recognising class I HLA) T cells (Figure 10.5). T cells all look much the same under light microscopy, and therefore, to distinguish them, flow cytometry is used to identify clusters of surface antigen that differentiate them (ie clusters of differention or ‘CD’ markers). All T cells express CD3, whereas CD4 is conserved among helper cells and CD8 is found on cytotoxic cells. Figure 10.5 Example of T-cell recognition of antigen via HLA T-helper cells T-helper cells can further be separated out into subtypes including Th1, Th2 and Th17 cells. Th1 Think of this as a more ‘aggressive’ phenotype, with a prominent inflammatory response, triggered by cytokines such as IFN, and resulting in a hostile environment for pathogens. Th2 The Th2 phenotype represents a more tolerant response, with cytokines such as IL-10 present (see Table 10.1), and is associated with a humoral response, driving antibody class switching. Pregnancy is a good example of when the Th2 phenotype predominates. Th17 This is a relatively recently described Th subtype, and seems pivotal in driving autoimmune disease. IL-17 is the key driving cytokine, and both Th17 and IL-17 are the current subjects of pharmaceutical trials across a broad range of diseases. Watch this space! T cells provide the immune system a ‘window’ into other cells, and are an especially important defence against intracellular pathogens. In the same way, the normal function of T cells is essential to prevent autoimmunity: unsurprisingly many of the genetic predictors of autoimmune disease lie in the genetic code for HLA on chromosome 6 (eg HLA-DR4 in rheumatoid disease, HLA-Cw6 in psoriasis). HIV infection HIV is the archetypal T-cell deficiency state. Specifically, the HIV virus leads to progressive depletion of the CD4 cell population. It is important to recognise the patterns of infections seen in HIV as a model of T-cell deficiency, and at this point refer to Table 10.1 – where you will recall IL-2 is a cytokine central to T-cell proliferation. Suppression of IL-2 effectively induces a T-cell-deficient state: one might rightly predict the same patterns of opportunistic infection in patients on tacrolimus and ciclosporin as we observe in HIV (tuberculosis, Pneumocystis jirovecii, disseminated viral disease). 10.6 HYPERSENSITIVITY Hypersensitivity reactions are immunological responses with excessive or undesirable consequences that may result in tissue or organ damage. There are five types (there used to be only four, but there was concern that the list was not long enough for MRCP candidates) (Table 10.3). 10.6.1 Latent tuberculosis screening Screening for latent tuberculosis (TB) relies on the tuberculin skin test (using either the Mantoux or the Heaf method). This was an example of a type IV hypersensitivity reaction – and highlights the delayed nature of the response. If an individual reacts to a tuberculin skin test in the first 24 hours, it implies allergy to protein rather than latent TB. After innoculation, patients need to return for the skin test to be read 48–72 hours after injection, and only if the response is delayed does it imply latent TB. A complicating factor in skin testing for latent TB is that many people have been exposed to the BCG immunisation, which is a live attenuated Mycobacterium bovis strain. Prior BCG immunisation can result in false-positive skin tests. To get around these issues, the interferon-γ release assays (IGRAs) have been developed (eg QuantiFERON or T Spot). These tests offer an in vitro alternative to the skin test, and use proteins that are unique to M. tuberculosis (and not present in M. bovis) to stimulate cytokine (IFN) release. IGRAs are NICE (National Institute for Health and Care Excellence) approved for screening for latent TB (but are not currently recommended for use in diagnosing active TB). Table 10.3 Hypersensitivity reactions Type Pathophysiology Example MRCP notes I Mast cell degranulation, histamine release, IgE Anaphylaxis, hay fever, asthma Immediate onset II Direct antibody-driven cytotoxicity Autoimmune haemolytic anaemia, Goodpasture syndrome Beware Graves’ diseasea III Immune complex deposition Extrinsic allergic alveolitis, Hypocomplementaemia often SLE present IV Cell-mediated (ie T-cell driven) BCG immunisation, graftversus-host disease V Stimulating/inhibiting Graves’ disease, myasthenia Tissue damage does not gravis occur Delayed onset aIn Grave’s thyroid disease, antibodies stimulate the thyroid gland (as oppose to destroy it) – therefore Grave’s disease is classed as a type V reaction. However, Grave’s eye disease does involve cytotoxicity, and is an example of a type II reaction. BCG, bacille Calmette–Guérin; SLE, systemic lupus erythematosus. 10.7 TRANSPLANTATION Transplantation has evolved enormously over the last 50 years. A xenograft is a transplant across different species (eg porcine heart valve), an allograft is within species, whereas an autograft is within the same individual. From an immunological perspective it is important to consider whether the transplant is immunogenic. Cardiac valve transplants are non-immunogenic and therefore do not require immunosuppression. Almost all other tissues transplanted are potentially immunogenic, and will usually require some form of immunosuppression. In the setting of organ transplantation, this will prevent host rejection. In the setting of a bone marrow transplant (where effectively the immune system is the organ that has been transplanted), immune suppression is to prevent graft-versus-host disease. A key principle in minimising the risk of rejection is to transplant tissue from an individual with as closely matched HLA genotypes as possible. The importance of HLA matching depends upon the immunogenicity of the tissue being transplanted. HLA matching is very important for renal transplantation, whereas it is relatively unimportant for liver transplantation (Table 10.4). 10.8 IMMUNODEFICIENCY Primary immunodeficiency is rare, and usually the diagnostic remit of paediatricians. However, it is important to remember that secondary immunodeficiency due to disease or medication is common, encountered by adult physicians on a daily basis in routine practice. 10.8.1 Patterns of infection in immunodeficiency Neutrophil defects These result from recurrent bacterial or fungal skin infections (cellulitis/abscesses). Examples • Primary: chronic granulomatous disease • Secondary: diabetes mellitus. Complement deficiency Complement deficiency may be uncovered incidentally, and is not always symptomatic. The most important clinical associations with complement deficiency include hereditary angioedema and SLE. When infections occur it usually implies a final common pathway defect manifesting with recurrent/invasive Neisseria spp. infections. Table 10.4 Transplant rejection key facts Type Mechanism Timing of onset Clinical features Hyperacute Pre-existing humoral immunity Immediate (ie while still on Severe systemic the operating table) inflammatory response Acute T-cell driven Weeks to months Most patients experience some form of rejection. In its severe form it is characterised by photosensitive rash, abdominal pain and jaundice Chronic Variable (including noncompliance with Months to years medication) Occurs after repeated episodes of acute rejection. A problem especially in lung transplantation Examples • Primary: inherited final common pathway deficiencies Secondary: eculizumab (C5 inhibitor used for treatment of paroxysmal nocturnal • haemoglobinuria [PNH]). B-cell/antibody deficiency This results in sinopulmonary infections/bronchiectasis. Examples Primary: common variable immunodeficiency, selective IgA deficiency, Bruton’s hypogammaglobulinaemia • Secondary: chronic lymphocytic leukaemia, rituximab, gold, phenytoin. • T-cell deficiency These include opportunistic infections, eg Pneumocystis jirovecii, invasive viral infections (cytomegalovirus [CMV]), intracellular bacterial infections (eg salmonellae) and mycobacterial infections. Examples • Primary: DiGeorge syndrome, severe combined immune deficiency (SCID), ataxia telangectasia • Secondary: HIV infection, ciclosporin, anti-CD3 therapy. Job syndrome (hyper-IgE syndrome) This rare disease acquired its name after Job in the Bible, who was plagued with boils. The syndrome is characterised by multiple immune failures affecting both innate and adaptive responses. A common mnemonic used to remember the symptoms is FATED: coarse or leonine facies, cold Staphylococcus spp. abscesses, retained primary teeth, increased IgE, and dermatological problems (eczema). The key abnormality is a failure of intracellular signalling in the JAK-STAT pathway. Clinical manifestations are heterogeneous; however, it is one of the very few diseases that is associated with cryptococcal pneumonia (Cryptococcus neoformans usually invades only the CNS tissue). The reason for mentioning this is that the JAKSTAT pathway has been earmarked as the next major immune pathway to inhibit in the treatment of autoimmune diseases. The US Food and Drug Administration (FDA) licensed the first JAK inhibitor in 2012, and there have already been reports of cryptococcal pneumonia. 10.9 IMMUNISATION The principles underpinning immunisation date back to the nineteenth century when Edward Jenner published the first description of vaccination against smallpox. Vaccination or immunisation has contributed immeasurable benefits to society, while continuing to remain a controversial topic in the public eye. Scandal has surrounded the use of vaccine for over a century. For those who scorn sceptics of the MMR (measle, mumps, rubella) vaccine, it is worth remembering that vaccine supporters have not always been on the right side of the fence, eg in 1906 a cholera vaccine study accidentally muddled vaccine serum with bubonic plague serum, and infected and killed 13 study participants. However, there is no need to dwell on that. Instead remember the near eradication of polio in the world (Figure 10.6). 10.9.1 Principles of immunisation Immunity against a specific pathogen can be artificially generated either actively or passively. Passive immunisation involves the administration of preformed antibodies against a particular agent, eg varicella or rabies immunoglobulin. This approach has the advantage of providing instantaneous (within 24–48 hours) immunity – hence this approach is used as an immediate post-exposure prophylaxis. Figure 10.6 Worldwide annual incidence of polio (data from the World Health Organization) The disadvantages of passive immunity are twofold: 1. Immunity only lasts for the half-life of the immunoglobulin (30 days) 2. As a blood-derived product, there is a risk of transmissible disease. The principle of active immunisation is to expose the adaptive immune system to a stimulus (virus, bacteria or toxin) to generate a lasting response. The most common vaccines use killed whole organisms (the annual flu jab) or subunits or organisms (the polysaccharide pneumonococcal vaccine: Pneumovax). Some antigens are inherently less immunogenic, and in these settings a live virus is sometimes used (yellow fever vaccine, BCG vaccine, MMR). However, live vaccines must NOT be given to people who are immunodeficient (primary or secondary immunodeficiency). Another approach to improving the immunogenicity response of a vaccine is to conjugate a polysaccharide vaccine with a protein (eg conjugate pneumococcal vaccine – Prevenar). Conjugation stimulates a cellular immune response, improving the likelihood of protective immunity. For a list of the important vaccines for MRCP, see Table 10.5. Finally, remember no vaccine is 100% effective, and most immunisations rely on the principles of herd immunity. The concept of herd immunity relies on the premise that for infections to gain ground in a population they need to spread in chains from one person to the next. If a significant proportion of the population has reduced susceptibility, then these chains fail to develop and infection rates diminish in both vaccinated and unvaccinated individuals. Table 10.5 Design of vaccines in common use Passive Active Preformed antibodies Live vaccines Killed vaccines Subunit vaccines Tetanus Varicella Rabies Hepatitis B Yellow fever MMR BCG Varicella Oral polio (no longer available in the UK) Seasonal flu Typhoid Rabies Pertussis Cholera Parenteral polio Pneumococcus Hib Hepatitis B Meningococcus Botulism Diphtheria Hib, Haemophilus influenzae type b; HPV, human papilloma virus. HPV Chapter 11 Infectious Diseases and Tropical Medicine CONTENTS 11.1 Classification of bacteria and viruses 11.1.1 Bacteria 11.1.2 Viruses 11.2 Treatment and prevention of infections 11.2.1 Antibacterial agents 11.2.2 Other agents used to counteract infection 11.3 Infections in specific situations 11.3.1 Pregnancy and congenital infections 11.3.2 Intravenous drug use 11.3.3 Splenectomy 11.3.4 Sickle cell disease 11.3.5 Other factors predisposing to specific infections 11.4 Systemic infections and sepsis 11.4.1 Sepsis 11.4.2 Toxic shock syndrome 11.5 Infections of major systems 11.5.1 Respiratory infections 11.5.2 Neurological infections 11.5.3 Gastrointestinal infections 11.5.4 Cardiac infections 11.5.5 Skin and soft tissue infections 11.6 Mycobacterial infections 11.6.1 Tuberculosis 11.6.2 Non-tuberculous mycobacteria 11.7 Specific tropical infections 11.7.1 Malaria 11.7.2 Enteric fever (‘typhoid’) 11.7.3 Amoebiasis 11.7.4 Schistosomiasis (‘bilharzia’) 11.7.5 Leprosy 11.7.6 Lymphatic filariasis 11.7.7 Filariasis, including onchocerciasis 11.7.8 Cysticercosis 11.7.9 Trypanosomiasis 11.7.10 Leishmaniasis 11.7.11 Hookworm 11.7.12 Strongyloidiasis 11.7.13 Dengue fever 11.7.14 Viral haemorrhagic fevers 11.7.15 Rickettsial infections 11.7.16 Approach to fever in the returning traveller 11.8 Important zoonoses 11.8.1 Brucellosis 11.8.2 Lyme disease 11.8.3 Q fever 11.8.4 Toxoplasmosis Infectious Diseases and Tropical Medicine 11.1 CLASSIFICATION OF BACTERIA AND VIRUSES 11.1.1 Bacteria Classification is largely based on microscopic appearance, staining characteristics and biochemical tests. For example, Gram staining differentiates bacteria based on differences in cell wall thickness and therefore retention of the stain. Some relevant bacteria are classified here; more clinical detail is given in other sections as infections affecting the systems are discussed. Classification according to Gram staining and aerobic/anaerobic metabolism is shown in Table 11.1. Table 11.1 Gram staining and aerobic/anaerobic metabolism Gram positive Staphylococcia (in clusters) Aerobic cocci Streptococcib (in chains) Enterococci Aerobic bacilli Gram negative Moraxella sp. Neisseria sp. (eg N. meningitidis, N. gonorrhoeae, both Gramnegative diplococci) Listeria monocytogenes Nocardia spp. Enterobacter sp. Escherichia coli Corynebacterium diphtheriae Klebsiella sp. Proteus Bacillus cereus Salmonellae (including S. typhi) Shigella sp. Yersinia sp. Anaerobic bacilli Clostridia (including C. difficile, C. perfringens) Bacteroides sp. aStaphylococci are further classified, by the coagulase test, into S. aureus (coagulase-positive) and ‘coagulase-negative staphs’, often skin contaminants when grown in blood cultures, most commonly S. epidermidis, but can cause pathology. Staphs are mostly resistant to penicillins due to production of β-lactamases and are treated with β-lactamase-resistant penicillins such as meticillin and flucloxacillin, or with antibiotics including a β-lactamase inhibitor, such as co-amoxiclav. Meticillin-resistant S. aureus (MRSA) requires treatment with other antibiotics, including the glycopeptides vancomycin and teicoplanin, which are also active against other Gram-positive organisms. bStreptococci are further classified by the type of haemolysis seen on blood agar: α, β or γ haemolysis. Viridans-type streptococci are mostly α-haemolytic and commonly cause endocarditis. α-Haemolytic streptococci (and others) are classified using Lancefield groups. The most important β-haemolytic streptococci are given in Table 11.2. Table 11.2 Lancefield classification of important β-haemolytic streptococci Lancefield group Name Clinical relevance S. pyogenes Cellulitis Necrotising fasciitis Pharyngitis and tonsillitis Rheumatic fever (immunological reaction to pharyngeal infection) Glomerulonephritis (post-streptococcal infection, >1 week after infection) Scarlet fever (toxin-mediated) B S. agalactiae Puerperal and neonatal sepsis (therefore intrapartum antibiotics are given in some circumstances if detected in pregnancy) D Previously ‘enterococci’ Includes S. bovis, which causes infective endocarditis associated with colonic cancer A Bacteria that are not identified by Gram stain are often diagnosed by serology or other stains (Table 11.3). Table 11.3 Classification by serology or stains other than Gram stain Obligate intracellular bacteria Chlamydia spp. Coxiella spp. Rickettsia spp. Legionella spp. No cell wall Mycoplasma spp. Spirochaetes (coiled bacteria) Borrelia burgdorferi Leptospira sp. Treponemes (eg T. pallidum, which causes syphilis) 11.1.2 Viruses Viruses are classified according to whether their genetic material is DNA or RNA, aspects of their structure and replication cycle. Important examples are given here. The herpes viruses are double-stranded DNA viruses and include herpes simplex viruses 1 and 2 (HSV1 and HSV2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV) and human herpesvirus 8 (HHV8). Diagnosis is by polymerase chain reaction (PCR) or serology. Their clinical associations are described in Table 11.4. Pox viruses are also double-stranded DNA viruses and include smallpox (‘variola’; declared eradicated in 1979) and the molluscum contagiosum virus. Table 11.4 Clinical associations of herpesviruses HSV1 Initial infection may be asymptomatic or present with gingivostomatitis; leads to lifelong latency and recurrence as herpes labialis (cold sores) HSV2 Genital herpes with lifelong latency and recurrences HSV1 and -2 (1>2) cause aseptic meningitis or encephalitis, localised to the temporal lobes. Diagnosis of encephalitis is by PCR for HSV on CSF, along with MRI of the brain. Treatment is with intravenous aciclovir. In utero infection can cause severe malformations and neonatal infection has a high mortality VZV Primary infection is chickenpox (varicella) with an incubation period of around 14 days. The virus is then latent in the sensory ganglia Reactivation causes shingles (more common in immunocompromised individuals) Complications of chickenpox are more common in adults and include pneumonitis, especially in smokers. Permanent calcification can be seen on the chest radiograph. Cerebellar ataxia (due to VZV encephalitis) is rare CMV Primary infection is often asymptomatic (or causes a glandular fever-type syndrome, which may be complicated by Guillain–Barré syndrome or Bell’s palsy) and seroprevalence is >80% by age 60. CMV is problematic if the individual becomes immunosuppressed, eg after a transplantation or chemotherapy, or due to HIV infection. In HIV-infected individuals with low CD4 counts, CMV can cause sight-threatening retinitis, oesophagitis, colitis, hypoadrenalism, neuritis, CNS disease and cholangitis. Treatment is with antivirals, eg ganciclovir EBV Primary infection causes glandular fever (infectious mononucleosis or IM) and the virus is then latent in B cells, sometimes causing transformation to lymphoma. Adult seroprevalence is >90% and around 50% of acute infections cause symptomatic IM. It is associated with Burkitt’s lymphoma and lymphoma in HIV, nasopharyngeal carcinoma and oral hairy leukoplakia (white lesions of the lateral tongue borders in HIV) HHV8 Also known as ‘Kaposi’s sarcoma-associated virus’, this sexually transmitted virus is found in Kaposi’s lesions in HIV and in endemic Kaposi’s sarcoma. It is also associated with primary effusion lymphoma and Castleman’s disease in immunosuppressed individuals Retroviruses include the human immunodeficiency viruses (HIV-1 and HIV-2), plus human T-cell lymphotropic virus (HTLV-1). They are single-stranded RNA viruses, which replicate using reverse transcriptase and have DNA in their replication cycle. Proviral DNA integrates into the host genome, precluding eradication of these viruses to date. Hepatitis B and C have similarities in clinical disease, but are from different families: Hepatitis B is a DNA virus and hepatitis C is an RNA flavivirus. The term arbovirus is an abbreviation of ‘arthropod-borne virus’, and includes a varied group of organisms such as yellow fever and dengue viruses (RNA flaviviruses) and various causes of encephalitis (such as the flaviviruses causing West Nile and Japanese encephalitis, and the alphaviruses causing St Louis and Eastern equine encephalitis). 11.2 TREATMENT AND PREVENTION OF INFECTIONS 11.2.1 Antibacterial agents Antimicrobial groups, their mechanisms of action, indication, side-effects and mode of excretion are given in Table 11.5 (see also Chapter 2, Clinical Pharmacology, Toxicology and Poisoning). Table 11.5 Characteristics and uses of the main groups of antibacterial agents Antimicrobial group or Mechanism of action name Indications Side-effects Penicillins (eg benzylpenicillin)1 Block cell-wall synthesis Streptococci, respiratory infections, syphilis Anaphylaxis, interstitial nephritis (rare), encephalopathy (rare) Sulfonamides (eg sulfamethoxazole in co-trimoxazole) Co-trimoxazole in Inhibit enzymes pneumocystis converting ppneumonia prophylaxis aminobenzoic acid and treatment. (PABA) into folic acid Sulfadiazine in (antifolate) combination for toxoplasmosis Agranulocytosis, bone marrow suppression, Stevens–Johnson syndrome Aminoglycosides (eg gentamicin) Gram-negative infections, synergistic action in streptococcal Inhibit bacterial protein endocarditis. synthesis Tobramycin used for Pseudomonas and amikacin for mycobacteria Ototoxicity, renal tubular damage (monitor levels to avoid toxicity) Tetracyclines (eg doxycycline) Photosensitivity, renal Respiratory infections, impairment, deposition Inhibit bacterial protein Rickettsia sp., Q fever, in growing teeth and synthesis malaria prophylaxis bones, dental hypoplasia Cephalosporins (eg ceftriaxone) Block cell-wall synthesis Macrolides (eg erythromycin) Inhibition of bacterial protein synthesis Streptococci and Gramnegative infections, Anaphylaxis meningitis Gram-positive infections, atypical pneumonias, Thrombophlebitis, Mycobacterium avium cholestatic hepatitis (clarithromycin, in combination) Inhibit cell-wall synthesis Gram-positive infections, MRSA, C. difficile (vancomycin) Nephrotoxicity, ototoxicity, ‘red man’ syndrome (vancomycin) Inhibit bacterial DNA synthesis Gram-negative infections, TB in combination, gastrointestinal infections Hallucinations, psychosis, reduced seizure threshold, tendon damage and inflammation Block cell-wall synthesis Severe or resistant infections including extended spectrum betalactamase (ESBL)- Imipenem can induce producing bacteria. seizures Meropenem used for central nervous system infections Inhibits protein synthesis Skin and soft tissue infections including necrotising fasciitis; bone and joint infections Oxazolidinones (eg Linezolid) Inhibits protein synthesis Effective against Grampositive organisms Cytopaenias/bone including MRSA. Skin marrow suppression and soft tissue infections, pneumonia Metronidazole and tinidazole Production of free radicals in anaerobic microorganisms Anaerobic infections including abdominal sepsis. Amoebiasis, giardiasis, C. difficile Blocks cell membrane function Gram-positive skin and Creatine kinase soft tissue infections; S. elevation: measure CK aureus bacteraemia or at baseline and regular endocarditis, including intervals during therapy MRSA Tigecycline (a newer tetracycline) Inhibits bacterial protein translation Skin and soft tissue infections; abdominal sepsis (without bacteraemia) Pancreatitis, elevated transaminases Fidaxomicin Inhibits RNA synthesis C. difficile associated diarrhoea Nausea, vomiting Glycopeptides (eg vancomycin) Quinolones (eg ciprofloxacin) Carbapenems (eg meropenem) Clindamycin Daptomycin Antibiotic-associated colitis Disulfiram-like effect with alcohol. Cytopaenias 1 Antipseudomonal penicillins (eg piperacillin-tazobactam) used for severe Pseudomonas infections, often in combination. Pivmecillinam effective against Gram negatives, including E. coli, and used for uncomplicated urinary tract infections. 11.2.2 Other agents used to counteract infection Immunoglobulins Normal human immunoglobulin has many applications, particularly in passively immunising patients with humoral immunodeficiency. Kawasaki’s disease (possibly due to an infectious agent) is one application. There are also specific immunoglobulins for specific situations (eg tetanus, rabies, diphtheria, hepatitis B and varicella-zoster immunoglobulin). Vaccines The UK vaccination schedule aims to provide protection for children against the following infections: • • • • • • • • • • • • Diphtheria Tetanus Pertussis Haemophilus influenzae type b Polio N. meningitidis serogroup C Measles Mumps Rubella S. pneumoniae Human papillomavirus types 16 and 18 Rotavirus. Older adults are offered influenza and shingles vaccine. Immunisation of individuals with chronic medical conditions HIV infection: inactivated vaccines are given according to schedule although response may be suboptimal, depending on CD4 count. Some live vaccines (BCG, oral polio) are contraindicated in HIV infection. Others (yellow fever, MMR, varicella) are given only if the individual is asymptomatic and the current CD4 count is >200 cells/mm3. Chronic respiratory, heart, renal, liver disease and diabetes: annual influenza vaccine; single pneumococcal vaccine. (See also Chapter 10, Immunology.) 11.3 INFECTIONS IN SPECIFIC SITUATIONS 11.3.1 Pregnancy and congenital infections Infections exacerbated by pregnancy • • • • • • Urinary tract infection Salmonella spp. Listeria spp. Varicella (pneumonitis is life-threatening, especially in third trimester) Hepatitis E (25% mortality rate) Falciparum malaria Other infections important in pregnancy Transplacental transmission may lead to fetal damage. • • • • • Rubella: adults may be symptomatic of infection, with headache, fever, upper respiratory symptoms and a rash. First trimester infection leads to congenital rubella syndrome, with deafness, cataracts and patent ductus arteriosus. Some have less severe features initially but may have developmental delay Toxoplasmosis: infection in early pregnancy can cause miscarriage, and in later pregnancy, chorioretinitis, intracerebral calcification, psychomotor retardation and learning disability, jaundice and fever (see Section 11.8.4) CMV: often asymptomatic and mild in pregnant women, primary CMV infection infects 30–40% of fetuses, with increased risk of fetal injury in early pregnancy. It may cause intracerebral calcification, hepatosplenomegaly, retinitis and pulmonary infiltration Varicella (chickenpox): infection in early pregnancy causes congenital varicella syndrome, with limb hypoplasia and scarring of dermatomes. Pregnant women with varicella have a higher risk of pneumonitis than other adults. If a pregnant woman is exposed to varicella and is unsure of her history, serum should be tested for varicella IgG and, if negative, varicella-zoster immunoglobulin (VZIg) can be given to prevent infection Parvovirus B19: first trimester infection causes fetal anaemia, hydrops fetalis and fetal death. 11.3.2 Intravenous drug use Endocarditis: repeated injection into veins carries a risk of right-sided endocarditis. Infections in intravenous drug users can be polymicrobial – often Staphylococcus aureus, less commonly • streptococci and enterococci. Tricuspid valve endocarditis can lead to septic embolisation into the pulmonary circulation, causing pneumonia with patches of consolidation in both lungs (which may cavitate). See Section 11.5.4 and Chapter 1, Cardiology Blood-borne viruses: sharing of needles or any other equipment leads to transmission of HIV, hepatitis B and hepatitis C. Up to half of people who inject drugs in the UK have been infected • with hepatitis C (antibody positive). A positive hepatitis C PCR test, detecting viral RNA, is • • • • required to diagnose current infection (a positive antibody test only indicates exposure). (See also Chapter 6, Gastroenterology) Soft tissue infections: infections at injection sites, such as groin abscesses, are common, as is limb cellulitis, and there is a risk of gas gangrene (see Section 11.5.5) Clostridial infections: although more commonly seen in other groups, disease due to the Grampositive bacilli, C. botulinum and C. tetani, has recently increased in incidence among intravenous drug users Botulism: C. botulinum produces a toxin that causes the clinical syndrome of botulism. It is usually transmitted through food contaminated with the toxin. However, wound botulism can occur in intravenous drug users when the toxin is produced at the wound site. It causes an acute, descending (unlike Guillain–Barré syndrome), symmetrical, flaccid paralysis affecting primarily cranial and autonomic nerves, without fever. The incubation period (IP) is usually 12–72 hours and presenting symptoms may be blurred vision, diplopia, weakness, vomiting or urinary retention, progressing to respiratory failure requiring ventilation. There may be ophthalmoplegia and specific muscle weakness. Diagnosis is by detection of toxin and treatment with antibiotics (penicillin/clindamycin and metronidazole), plus supportive management Tetanus: tetanospasmin is the toxin produced by C. tetani, which travels via motor neurons to the central nervous system (CNS) where it blocks neurotransmitter release. C. tetani is a soil commensal and tetanus may be seen in elderly people, intravenous drug users or other individuals who have been incompletely immunised. The IP is 3–21 days. Trismus (lockjaw) may be followed by restlessness, irritability, dysphagia, opisthotonus (extreme hyperextension of the neck, back and lower limbs caused by spasm of skeletal muscles) and seizures. Diagnosis is clinical, plus culture or PCR to detect the organism. Treatment is with anti-tetanus immunoglobulin, wound debridement if required and antibiotics with action against anaerobes. Immunisation is by three doses of tetanus toxoid as a primary course, and then repeat doses every 10 years until five doses in total have been given. 11.3.3 Splenectomy The spleen accounts for approximately 25% of all lymphatic tissue; absence of its function causes particular vulnerability to systemic infection with capsulate organisms, such as: • S. pneumoniae • H. influenzae • N. meningitidis Capnocytophaga canimorsus, a Gram-negative bacillus characteristically acquired from dog • bites. Splenectomised patients are also vulnerable to malaria and babesiosis (Babesia spp.), a protozoal infection transmitted by ixodid ticks (as is Lyme disease, see Section 11.8.2) from an animal reservoir comprising small rodents (North America) or cattle (Europe). Babesiosis causes a mild malarialike disease in immunocompetent individuals, but is potentially life-threatening in splenectomised individuals. Diagnosis is by blood film. Immunisations and prophylaxis in splenectomised individuals Immunisation against H. influenzae type b, N. meningitidis group C and S. pneumoniae is recommended, as is an annual influenza vaccine Antibiotic prophylaxis with penicillin (or erythromycin if allergic) is required until at least age • 16 or for at least 2 years after a splenectomy. Appropriate malaria prophylaxis is vital if travelling to an endemic area. • 11.3.4 Sickle cell disease Sicklers (ie those who are SS homozygotes) often have functional hyposplenism and also a reduction in complement-mediated serum-opsonising activity. This gives rise to vulnerability to: • Pneumococcal infection (and other encapsulated organisms such as meningococci) • Other forms of bacterial sepsis – pneumonia and meningitis in particular • Osteomyelitis (due to Salmonella spp.) Morbidity and mortality from falciparum malaria, which precipitates haemolytic and infarctive • crises (in contrast to AS heterozygotes, who are relatively resistant to malaria) • Parvovirus B19 can cause life-threatening aplastic anaemia in sickle cell homozygotes. 11.3.5 Other factors predisposing to specific infections There are some host factors conferring susceptibility to sepsis of particular cause: 1. Deficiency of mannose-binding lectin and pneumococcal sepsis 2. Terminal complement deficiencies and meningococcal sepsis 3. Agammaglobulinaemia and pneumococcal and H. influenzae type b sepsis Chédiak–Higashi syndrome (a rare autosomal recessive condition with recurrent bacterial 4. infections) Leukocyte adhesion deficiency syndromes (genetically determined conditions with recurrent, 5. severe bacterial infections) Job’s syndrome (also known as hyperimmunoglobulin E syndrome: a primary immunodeficiency 6. associated with bacterial, especially staphylococcal, viral and fungal infections). 11.4 SYSTEMIC INFECTIONS AND SEPSIS 11.4.1 Sepsis Sepsis is a systemic, deleterious host response to infection. To aid immediate clinical management, grades of severity are defined as follows: SIRS (systemic inflammatory response 2 or more of: Fever >38 or <36°C Heart rate >90 beats/minute Respiratory rate >20 breaths/minute or pCO2 <32mmHg White cell syndrome) Sepsis Severe sepsis Septic shock count >12,000/μL or <4,000/μL or >10% immature forms The association of SIRS with evidence or suspicion of a microbial origin Acute organ dysfunction secondary to documented or suspected infection Severe sepsis plus hypotension not reversed with fluid resuscritation SIRS is therefore not always associated with bacteraemia and bacteraemia does not always cause SIRS. Shock is the result of a cascade of inflammatory mediators such as tumour necrosis factor (TNF) and interleukin-1 (IL-1), and the origin is usually bacterial, although often not confirmed by culture, but can be due to other infectious agents (eg fungi) or non-infectious causes. Early antibiotic treatment and supportive care are the mainstays of management. International guidelines from the ‘‘Surviving sepsis campaign’’ recommend early goal-directed therapy in the first 6 hours to improve outcomes, plus completion in the first hour after presentation of the ‘sepsis six’. Sepsis six 1. High-flow oxygen 2. Blood cultures (and other relevant samples) 3. Broad-spectrum antibiotics 4. Intravenous fluid challenge 5. Measure serum lactate and Hb 6. Commence accurate hourly urine-output measurement 11.4.2 Toxic shock syndrome Toxic shock syndrome is an acute, multisystem, toxin-mediated illness, with fever, rapid-onset hypotension and multiorgan failure. The majority of cases are caused by toxin-producing strains of Staphylococci or Streptococci. Toxic shock has been associated with tampon use in menstruating women, but can be due to other staphylococcal foci, eg surgical wound infection or abscess. Toxin-producing Staphylococcus aureus (producing, for example, toxic shock syndrome toxin-1 [TSST-1] or staphylococcal enterotoxin B) is usually implicated, but a similar syndrome can follow infection with exotoxin-producing streptococci (eg invasive group A streptococci/S. pyogenes). Clinical features: fever, diffuse macular rash (followed by desquamation after 10-21 days in • staphylococcal TSS), hypotension, plus evidence of multiorgan involvement such as vomiting or diarrhoea, renal failure, thrombocytopenia or altered mental state Diagnosis: organisms may not be identified on culture, particularly in staphylococcal TSS, so • treatment is on suspicion and exclusion of other causes of shock, eg meningococcaemia Treatment: Antibiotic therapy should include agents targeting suspected organisms, including consideration of drug-resistant organisms such as MRSA, plus an agent that suppresses toxin production, such as clindamycin or Linezolid. Urgent surgical debridement may be required if • there is necrotising fasciitis or myositis. Supportive care is the mainstay of treatment. There is some evidence for the use of intravenous immunoglobulin and this can be considered if other approaches are failing in the initial hours of treatment. 11.5 INFECTIONS OF MAJOR SYSTEMS 11.5.1 Respiratory infections Most respiratory conditions are covered in Chapter 19, Respiratory Medicine. Some specific infections are covered here. For mycobacterial infections, see Section 11.6. Infectious mononucleosis (See also Section 11.1.2.) Infectious mononucleosis (IM) (also known as glandular fever) is caused by EBV, which is transmitted by saliva. Asymptomatic viral shedding is common and the IP is 30–45 days. Symptoms are sore throat, fever and malaise, with signs of exudative tonsillitis, lymphadenopathy and sometimes splenomegaly or a widespread maculopapular rash. An associated EBV hepatitis can cause jaundice. Treatment with ampicillin (often for presumed streptococcal infection) causes a maculopapular rash. Possible complications include thrombocytopenia, haemolytic anaemia, traumatic rupture of an enlarged spleen and, rarely (<1%), Guillain–Barré syndrome, cerebellar ataxia, aseptic meningitis, encephalitis, pneumonitis, pericarditis or lymphoma. Diagnosis IM causes a lymphocytosis, with atypical lymphocytes seen on the blood film, positive monospot (Paul–Bunnell) test for heterophile antibodies, and increased transaminase and bilirubin levels if there is associated hepatitis. Specific tests for EBV are also positive, including antiviral capsid IgM in recent infection. Treatment There is no specific treatment. Steroids are given if tonsillitis threatens airway obstruction. Differential diagnosis of glandular fever (IM) Includes acute CMV, toxoplasmosis, primary HIV infection, plus other causes of pharyngitis such as group A streptococcal infection or diphtheria Diphtheria Corynebacterium diphtheriae (or C. ulcerans in some cases) is a spore-forming, Gram-positive bacillus that can produce an exotoxin. It is transmitted by respiratory droplets. It is very rare in the UK due to the immunisation schedule, which includes diphtheria immunisation along with tetanus, polio, Haemophilus influenzae type b (Hib) and pertussis before 12 months of age. It occurs more frequently in countries with lower immunisation coverage. The IP is 2–5 days and infection presents with fever, anterior cervical lymphadenopathy and soft tissue oedema, giving a ‘bull neck’ appearance and a membranous pharyngitis; the grey, fibrinous ‘pseudomembrane’ may cause airway obstruction. In immunised individuals, milder infection may resemble streptococcal pharyngitis. The exotoxin can rarely cause paralysis (peripheral neuritis) and myocarditis. Cutaneous diphtheria presents with a skin ulcer that may have an eschar. Diagnosis Culture of throat swab for corynebacteria should be specifically requested if infection is suspected. If cultured, organisms are sent for toxigenicity testing by PCR. Suspect infection in those who have travelled to endemic countries, had animal contact, are unvaccinated or are laboratory workers. Treatment Specific diphtheria antitoxin for suspected or confirmed cases, plus penicillin or erythromycin for 14 days. Immunise if this has not previously been done. Isolate the patient and notify public health authority so that contacts can be managed appropriately. Lemierre’s disease Tonsillitis caused by the anaerobe Fusobacterium necrophorum can spread to cause internal jugular thrombosis and secondary abscesses elsewhere, eg lungs. Diagnosis is by culture of pus or blood and prolonged antibiotics ± anticoagulation is required. ‘Atypical’ pneumonia This term is usually applied to pneumonias not conforming to a lobar pattern and ‘typical’ clinical features (symptoms and signs of acute lower respiratory tract infection, fever, focal chest signs and, if diagnosed in hospital, radiological features) and includes pneumonia caused by the following organisms: • • • • • Mycoplasma pneumoniae Legionella pneumophila Chlamydia pneumoniae Chlamydia psittaci (psittacosis) Coxiella burnetii (Q fever). Investigations for these infections differ from those for ‘typical’ pneumonia in that the organisms are not cultured from blood or sputum. Serological tests are required, ideally acutely and during convalescence, demonstrating an increasing antibody titre due to the infection. Urinary antigen detection is useful for L. pneumophila, particularly as it can give a rapid diagnosis, as early as 1 day after symptoms although it detects only serogroup 1, L. pneumophilia. For Q fever, see Section 11.8.3 Clinical features of pneumonia are described in Chapter 19, Respiratory Medicine, Section 19.3.1. 11.5.2 Neurological infections Infections of the brain and spinal cord can cause focal, space-occupying lesions, meningitis or encephalitis. The peripheral nerves are less susceptible to direct bacterial infection (with the exception of leprosy). Most bacterial infections that affect peripheral nerves do so by the action of specific toxins (eg botulinum, diphtheria). Some viruses (particularly enteroviruses, eg poliovirus) can damage peripheral nerves. Meningitis Acute meningitis presents with headache, fever and meningism. The level of consciousness is normal unless there is encephalitis. Urgent treatment (ceftriaxone or cefotaxime) is required for bacterial meningitis and UK guidelines now recommend glucocorticoid treatment (dexamethasone) with antibiotics; evidence is strongest for benefit in pneumococcal meningitis. Meningococcal disease may be in the form of meningitis or septicaemia, or both. In meningococcal septicaemia the diagnosis is made by blood culture and/or blood PCR for Neisseria meningitidis. Coagulopathy due to disseminated intravascular coagulation (DIC) may preclude lumbar puncture. Common causes of acute bacterial meningitis in adults are N. meningitidis (meningococcus), Streptococcus pneumoniae (pneumococcus) and Haemophilus influenzae. Listeria monocytogenes is an important, although less common, cause in elderly or very young people, and ampicillin should be added to cover this for adults over 55 years old. (See Section 11.1.1 for Gram-staining characteristics.) Spread from local ear, nose or throat infections is often implicated in pneumococcal meningitis. Cerebrospinal fluid (CSF) characteristics in meningitis are given in Table 11.6. Other causes of meningitis • Viral meningitis due to: • Enteroviruses (Coxsackieviruses A and B, echoviruses) • Herpesviruses (HSV1 and 2, EBV, VZV) • More rarely and characteristically with lymphocytic CSF • Leptospirosis (Leptospira spp.) • Syphilis (Treponema pallidum) • Lyme disease (Borrelia burgdorferi) • Fungal meningitis (eg Cryptococcus neoformans, Histoplasma capsulatum) Note on prophylaxis of contacts Antibiotic prophylaxis with rifampicin (licensed) or single-dose ciprofloxacin (unlicensed) is offered to close (household) contacts of an individual with meningococcal disease as soon as possible, ideally within 24 hours, after diagnosis of the index case, and to those who have had contact with respiratory droplets/secretions at the time of admission to hospital, eg staff involved in airway management Table 11.6 CSF characteristics in meningitis Appearance Cells Glucose Protein Organisms Acute bacterial Cloudy, turbid Viral Clear Neutrophils Lymphocytes ↑ ↓ ↔ ↑ ↑ or ↔ Tuberculous Cloudy/turbid Lymphocytes ↑ ↓ ↑↑ Cryptococcala Clear Lymphocytes ↑ ↑ or ↔ ↑ or ↔ On Gram stain/culture Not seen On Ziehl– Neelsen/auramine stain/culture India ink aOften high opening pressure. Encephalitis Encephalitis is inflammation of the brain parenchyma, often due to infection, including viruses, bacteria and fungi. There is an altered level of consciousness. In the UK, the most common cause is HSV (1>2). Prognosis with HSV encephalitis is much improved with prompt aciclovir treatment. Clinical features There may be fever and headache with focal (often temporal lobe) signs, or seizures or coma. Diagnosis Viral encephalitis is diagnosed by PCR on CSF. The EEG may show abnormalities in the temporal lobes and magnetic resonance imaging (MRI) may show enhancement of the temporal lobes. HIV testing is recommended for all individuals with possible encephalitis. Treatment Autoimmune encephalitis is an important differential if tests for infections are negative. Prompt treatment with aciclovir (requiring dose adjustment in renal impairment) reduces the mortality rate from up to 70% to around 25%. It also reduces long-term neurological disability. Infective causes of encephalitis • Viral • Herpes simplex (high mortality/morbidity, mainly type 1) • Measles, mumps • Enteroviruses, flaviviruses (eg Japanese encephalitis, West Nile) • VZV • HIV • Rabies • CMV and EBV in the immunocompromised • Others • Listeria (brainstem encephalitis) • Toxoplasmosis • African trypanosomiasis Space-occupying lesions Brain abscesses They often have an identifiable route of infection, such as recent surgery, parameningeal infection (otitis media, sinusitis, dental abscess) or metastatic spread from, for example, endocarditis, suppurative lung disease or congenital heart disease with right-to-left shunt. Organisms Often mixed, including one or more of: Staphylococcus aureus, Streptococcus milleri group, coliforms, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, anaerobes. Listeria monocytogenes causes brainstem abscesses or rhombencephalitis. Treatment Broad-spectrum initially, eg cephalosporin plus metronidazole, then antibiotic therapy guided by results of aspiration. Other focal lesions Neurocysticercosis (see Section 11.7.8), neuroschistosomiasis (see Section 11.7.4) and hydatid (see Section 11.5.3). Toxoplasmosis or cryptococcoma in immunocompromised individuals; tuberculomas; aspergillomas in those with disseminated aspergillus infection. (See also Chapter 16, Neurology.) 11.5.3 Gastrointestinal infections Bowel Most gut infections cause diarrhoea (Table 11.7); as a general rule, small-bowel infection usually manifests as toxin-mediated, watery diarrhoea with no blood whereas large-bowel infections (with exceptions) may be invasive of colonic mucosa and cause bloody diarrhoea with mucus and sometimes pus – ‘dysentery’. (See also Chapter 6, Gastroenterology.) Table 11.7 Organisms causing vomiting and/or diarrhoea Symptom Organisms Incubation Period Source Vomiting Diarrhoea Bacillus cereus 1–6 hours Staphylococcus aureus 2–7 hours Escherichia coli (enterotoxigenic) 12–72 hours Campylobacter jejuni 1–10 days Salmonella spp. Shigella spp. Yersinia enterocolitica 8–48 hours 12–96 hours 3–7 days Toxin from rice or meat Toxin from dairy or meat products From milk, salads, water (major cause of travellers’ diarrhoea) From meat, especially poultry, dairy products From eggs, poultry Faecal contamination From pork, dairy products Food poisoning should be notified to public health on suspicion. Other notifiable diseases • include malaria, meningococcal disease, measles, enteric fever, TB, viral hepatitis, tetanus and diphtheria Escherichia coli O157 Verotoxin-producing; may lead to epidemics of haemolytic uraemic syndrome. Amoebiasis See Section 11.7.3. Giardiasis The protozoon Giardia lamblia causes a minority of travellers’ diarrhoea. It is transmitted by ingestion of cysts from faecally contaminated water or person-to-person. The IP is 3–20 days and symptoms may persist for several weeks. Initially causing diarrhoea, symptoms may progress to nausea, cramps, abdominal pain, bloating and burping. Some individuals develop chronic diarrhoea with significant weight loss. Diagnosis Cysts seen on stool microscopy or trophozoites seen on biopsy of small-bowel mucosa. Treatment Tinidazole (2 g single dose) or metronidazole (eg 2 g daily for 3 days; different regimens vary from 3 days to 10 days) plus supportive treatments. Tropical sprue Also known as post-infective malabsorption. E. coli, and Klebsiella and Enterobacter spp. are implicated in causing this chronic (>2 months) malabsorption of nutrients, which may lead to haematinic and protein deficiency states. It is mostly found in south and south-east Asia. Cryptosporidiosis This is a protozoal infection (Cryptosporidium parvum) that causes watery diarrhoea. The IP is 2–14 days. It occurs in water-borne epidemics worldwide but may cause severe, prolonged, watery diarrhoea in immunosuppressed, particularly HIV-infected, individuals. There is no reliable antimicrobial therapy and, in HIV, treatment is aimed at restoring T-cell levels with antiretroviral therapy. Nitaxozanide has some effect in immunocompetent individuals and may be considered in the immunosuppressed, although evidence is weak. Diagnosis Red cysts on Ziehl–Neelsen staining of stool. Antibiotic-related diarrhoea and C. difficile Antibiotic-associated diarrhoea is mostly due to toxin-producing C. difficile, growth of which is increased by the reduction in normal bowel flora. C. difficile is a spore-forming, anaerobic bacterium. Spores are found in hospital environments and are secreted by affected patients or asymptomatic individuals. Severe disease can cause pseudomembranous colitis, toxic megacolon and perforation. C. difficile infection is an important issue in NHS hospitals, with targets for prevention, mandatory reporting and root-cause analysis of individual cases. It is associated with high levels of morbidity and mortality and optimal management is essential, including supportive management of patients with the disease. Risk factors for disease should be minimised in hospitalised patients where possible and include the following: • Older age Antibiotic use, including in the community (particularly broad-spectrum agents clindamycin, co• amoxiclav, ciprofloxacin, cephalosporins) • Proton-pump inhibitors/other acid-suppressing agents. Markers of severe disease are as follows: • • • • White cell count >15 × 109/L Acutely raised creatinine (50% above baseline) Temperature >38.5°C Evidence of severe colitis (eg abdominal signs, bowel distension on radiology). Elevated blood lactate is associated with very poor prognosis. Diagnosis Diarrhoeal stool should be sent for 2-stage testing for the presence of C. difficile and for toxin production. The first stage is a molecular (PCR) test or enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) to indicate the presence of the C. difficile organism. If this is positive, an EIA for toxin is done, indicating whether diarrhoea-producing toxin is present. Those with toxin present are treated for disease as shown below. Infection control measures are required for those with organism present but negative tests for toxin, who may have the potential to transmit C. difficile. Management Treatment includes supportive measures and antibiotic therapy, and severity should be reassessed frequently. Frequency and severity of diarrhoea can be monitored using the Bristol stool chart. Patients should be isolated if C. difficile infection is suspected and stool sent for testing immediately. Those with suspected severe disease should have surgical input. Treatment, according to severity, is summarised in the following Table 11.8, according to national guidelines. There is increasing trial evidence for the use of faecal transplant (‘faecal microbiota transplantation’ or enteric infusion of donor faeces) in recurrent C. difficile infection and NICE recommends consideration of such therapy for those failing to respond to other treatments. However, faecal transplant is not available in most centres. It requires donor screening for transmissible infections. Liver Amoebic liver abscess • See Section 11.7.3. Hydatid disease Echinococcus granulosus is a dog tapeworm. Ingested eggs from contact with dogs or contamination of food hatch into larvae and penetrate the bowel wall into the portal bloodstream. They mature into liver cysts and can also disseminate to other sites, eg lung, brain. Liver cysts present insidiously as a liver mass. Rupture can cause life-threatening anaphylaxis, and cysts must not be aspirated due to the risk of spreading the protoscolices around the body. People working with dogs or in sheep farming may be at risk. Table 11.8 Grades of severity or C. difficile Severity Stools (Bristol stool chart) White cell count Mild Moderate <3 of type 5–7 3–5/day Not raised Oral metronidazole 400–500 mg Raised but <15 × 109/L tds for 10–14 days Severe Not a reliable indicator >15 × 109/L Treatment Oral vancomycin 125mg qds for 10–14 days Consider fidaxomycin if high risk for recurrence In life-threatening cases, oral vancomycin up to 500mg qds for 10–14 days plus iv metronidazole 500mg tds Diagnosis Liver ultrasound, serology. Treatment Surgical removal of the cysts (with care not to spill contents into the abdominal cavity, because this can cause recurrence) and anthelmintic drugs, albendazole/mebendazole, praziquantel, pre- and postoperatively. Asymptomatic cysts may not need treatment. Leptospirosis This zoonotic spirochaete infection is transmitted by contact with the urine of infected mammals (dogs, rats) through broken skin, usually in contaminated water. There is often a history of occupational (sewage or agricultural workers) or recreational (fishing, water sports) exposure. Leptospira interrogans is the species responsible for disease. The IP is 7–12 days. Clinical features Usually headache, fever, myalgia, rigors and neck stiffness for 4–5 days due to leptospiraemia. Some recover after this phase, but for others, as the organism localises and causes vasculitis and capillary injury, further fever, suffused conjunctivae, aseptic meningitis and jaundice with renal impairment and proteinuria (Weil’s disease) follow. Some have cardiac involvement with arrhythmias or cardiac failure. There is typically a neutrophilia, raised creatine kinase (CK) and lymphocytic CSF. Diagnosis Culture of blood/CSF/urine, serology, PCR. Treatment Penicillin, tetracycline with supportive measures. (See Section 11.8 for other zoonoses.) Viral hepatitis See Chapter 6, Gastroenterology. 11.5.4 Cardiac infections Infective endocarditis Infective endocarditis is most commonly caused by bacterial infection affecting damaged or prosthetic heart valves, particularly streptococci, which colonise the mouth and upper respiratory tract. For example, viridans-type streptococci, a group including S. sanguis and S. oralis, are the most common cause of native valve endocarditis. Organisms may originate from dental disease or intravenous lines. Streptococcal endocarditis presents more indolently than staphylococcal endocarditis. Right-sided, staphylococcal endocarditis occurs in intravenous drug users, as above. Endocarditis is less commonly caused by the HACEK group of organisms (Haemophilus aphrophilus and H. paraphrophilus, Actinobacillus hominis, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae and K. denitrificans); fastidious Gram-negative organisms, or by Bartonella spp. or Q-fever (Coxiella burnetii). UK guidelines state that infective endocarditis must be considered in patients fulfilling the following criteria: • Fever and a murmur of new valvular regurgitation • Fever and a pre-existing at-risk cardiac lesion and no other apparent source of infection • Fever and: • Predisposition and recent intervention with associated bacteraemia • Evidence of congestive cardiac failure Vascular of immunological phemonema: embolic events, Roth spots, splinter haemorrhages, • Jameway lesions, Osler’s nodes • A new stroke • Peripheral abscesses (renal, splenic, cerebral, vertebral) of unknown cause • A protracted history of sweats, weight loss, anorexia or malaise, and an at-risk cardiac lesion • Any new, unexpected embolic events • Unexplained, persistently positive blood cultures Intravascular catheter-related bloodstream infection with persistently positive blood cultures 72 • hours after catheter removal. Echocardiogram should routinely be done in patients with S. aureus bacteraemia or candidaemia, in view of the higher likelihood of endocarditis. Diagnosis of infective endocarditis can be made using Duke’s criteria (see box). The importance of positive blood cultures in diagnosis and treatment means that samples must be taken before antibiotics are given. In those with chronic or subacute presentations, three sets of blood cultures should be taken with at least 6 hours between them, to confirm continuous bacteraemia. In very unwell patients, two sets with 1 hour between them should be taken before empirical therapy is started. Transthoracic echocardiogram (TTE) is the initial imaging of choice, to be followed by transoesophageal echocardiogram (TOE) if there is a prosthetic valve, if the TTE is of poor quality, positive, or negative in the context of continuing clinical suspicion. If blood cultures are negative, serology for Coxiella and Bartonella should be done, followed by Chlamydia, Legionella and Mycoplasma if these are negative, and Brucella if there is a history of potential exposure. Cases are ‘definite’ if they fulfil two major Duke’s criteria, one major and three minor, or five minor; ‘possible’ if they fulfil one major and one minor or three minor criteria: Major Duke’s criteria • Microbiological Typical infective endocarditis organism from two separate blood cultures (viridans-type • streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, communityacquired enterococcal bacteraemia without obvious source) OR • Organism consistent with infective endocarditis from persistently positive blood cultures OR • Single positive blood culture for Coxiella burnetii or serology positive for C. burnetii • Cardiological • New valvular regurgitation OR • Positive echocardiogram Minor Duke’s criteria • • • • • Predisposition to infective endocarditis (intravenous drug use, cardiac abnormality) Fever Vascular phenomena Immunological phenomena Positive blood cultures not meeting major criteria Treatment Empirical treatment for native valve endocarditis with indolent presentation, unless staphylococcal infection is suspected, is intravenous amoxycillin with synergistic doses of gentamicin (1mg/kg twice daily). For prosthetic valve endocarditis, vancomycin and gentamicin plus rifampicin are currently recommended. Regimens can be rationalised once the organism is identified and sensitivity testing completed. The duration of treatment depends on the organism; for some cases (eg uncomplicated streptococcal disease), 2 weeks of intravenous antibiotic may be sufficient. In staphylococcal endocarditis with a sensitive organism, flucloxacillin is recommended, and with likely or confirmed MRSA, vancomycin and rifampicin can be given. Antibiotic prophylaxis against endocarditis NICE guidelines recommend that antibiotic prophylaxis is no longer given routinely for invasive procedures, including dental, gastrointestinal or genitourinary procedures due to lack of proven efficacy. Pericarditis and myocarditis Pericarditis and myocarditis present with chest pain and typical widespread, concave ST elevation on the ECG. They are caused by viruses, including enteroviruses (eg Coxsackie viruses A and B and echoviruses). Pericarditis may be caused by bacteria in individuals with severe septic illness or by Mycobacterium tuberculosis, often in combination with pulmonary tuberculosis. Rheumatic fever Rheumatic fever is very rare in the UK, but occurs in developing countries. It is an immunological response to group A streptococcal infection. Although not a cardiac infection in itself, it is included here because of its association with later risk of endocarditis and initial carditis, which may include valvular disease. Diagnosis can be made according to the Jones’ criteria, by the presence of evidence of streptococcal infection plus either two major criteria or one major and two minor criteria, as shown in the following box. A Evidence of recent group A streptococcal infection • • Positive throat swab culture or streptococcal antigen test Elevated or rising streptococcal antibody titre B Major manifestations • • • • • Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules C Minor manifestations • • • • Arthralgia Fever Elevated acute-phase response (C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) Prolonged PR interval in ECG Q fever For Q fever, see Section 11.8.3. 11.5.5 Skin and soft tissue infections Staphylococcus aureus and Streptococcus pyogenes (Lancefield group A β-haemolytic streptococci, as in Table 11.2) are mainly responsible for community-acquired soft tissue infection in otherwise healthy patients. Necrotising fasciitis This is an acute necrotising infection of the skin, subcutaneous tissues and superficial fascia. It may involve muscle. Clinically there is soft tissue erythema or dusky appearance with severe pain. Risk factors are diabetes, advanced age, obesity and intercurrent illness. It is often a mixed infection, with Streptococcus pyogenes, anaerobes and coliforms. It requires aggressive surgical debridement as well as antibiotics (covering anaerobes, Gram negatives and streptococci; clindamycin may have benefit in inhibiting production of streptococcal toxins). Fournier’s gangrene is a type of necrotising fasciitis involving the male genitalia. Clostridial gas gangrene Muscles are involved in this infection with Clostridium perfringens or other clostridia. There is systemic illness and gas in the tissues. It often follows trauma or surgery with wound contamination. The organisms are anaerobic and so impaired perfusion increases risk of disease. Urgent debridement is required. 11.6 MYCOBACTERIAL INFECTIONS 11.6.1 Tuberculosis Mycobacterium tuberculosis disease, although most commonly pulmonary, can affect any organ. M. tuberculosis can also produce latent infection, said to affect a third of the world’s population, with the potential to reactivate and cause disease years later. Transmission is by respiratory droplets from an individual with smear-positive (‘open’) TB. Globally, TB control has been hampered by the HIV pandemic, which increases the risk of TB disease by impairing cell-mediated immunity. Other risk factors include contact with a known case of pulmonary TB, history of living in an institution (eg prison) and originating from a country with high incidence of TB disease. Current UK case notifications are around 14 per 100,000 population/year and have been stable since 2005 after previous increases. Around 1.5-2% of these are multidrug resistant, with 7.5% resistant to any one first-line drug. Note on drug-resistant tuberculosis Multidrug-resistant (MDR) TB is defined by resistance to at least isoniazid and rifampicin. Extensively drug-resistant (XDR) TB is MDR plus resistance to a fluoroquinolone (eg moxifloxacin, ciprofloxacin) and one of three injectable agents (kanamycin, capreomycin, amikacin). Drug-resistant TB occurs if treatment has been wrongly prescribed, intermittent or incomplete, with the strongest risk factor being previous TB treatment. The highest proportions of drug resistance among TB cases are found in eastern Europe, Russia and central Asia Diagnosis The mainstay of diagnosis is identification of acid-and alcohol-fast bacilli (AAFBs) in sputum, fluid (eg pleural fluid, pus) or tissue by Ziehl–Neelsen or auramine staining, and by culture to confirm M. tuberculosis (rather than a non-tuberculous mycobacterium) and to establish drug susceptibility. Culture is on Löwenstein–Jensen solid medium (taking up to 6 weeks) or in liquid culture media, in which mycobacteria grow more quickly, in up to 2 weeks, allowing faster confirmation of diagnosis. PCR is increasingly being used on some samples (sputum, CSF). Rapid PCR-based tests for genes conferring rifampicin and isoniazid resistance can give early indication of susceptibility. A test for a gene conferring rifampicin resistance (rpoB) is a useful indicator of probable MDR TB, as rifampicin monoresistance is rare. These tests do not replace culture and drug-susceptibility testing, which must also be done. Interferon-γ tests These blood tests measure the release of IFN-γ in the laboratory in response to antigens found only in M. tuberculosis (and not BCG or non-tuberculous mycobacteria). They are used to differentiate latent TB from a positive Mantoux test due to previous exposure or immunisation, but do not distinguish between active disease and latent infection. Their use is principally in assessing contacts of an index case or diagnosing latent TB in those at risk of reactivation, for example certain HIV-positive individuals and those planning immunosuppressive treatment, eg infliximab for rheumatoid arthritis. Latent infection can then be treated with isoniazid ± rifampicin. Interferon-γ tests are not useful in diagnosing active TB. Treatment Drug-susceptible TB is treated with rifampicin and isoniazid for 6 months, adding pyrazinamide and ethambutol for the first 2-month intensive phase (‘RIPE’). The exception is central nervous system TB disease, in which case the total treatment is 12 months, with a 2-month intensive phase and a 10month continuation phase (see Section 11.5.2 for CSF values in TB meningitis). Pyridoxine (vitamin B6) can be added to prevent peripheral neuropathy due to isoniazid. First-line anti-tuberculous drugs and their side-effects are summarised in Table 11.9. Drug-resistant TB is treated with individualised regimens comprising at least four second-line drugs to which the organisms is known or presumed to be susceptible. Regimens should contain fluoroquinolones, an injectable agent, prothionamide and other drugs depending on susceptibility testing. New anti-tuberculous agents are now finally emerging after decades with no or very little development. Table 11.9 First-line anti-tuberculous drugs Pharmacokinetics Side-effects Rifampicin Potent liver enzyme inducer – interactions with HIV drugs, methadone, steroids, anticoagulants TB, meningococcal Drug-induced hepatitis, prophylaxis, orange secretions, influenza- staphylococcal like syndrome infections, Legionella spp. Isoniazid Potentiates phenytoin, carbamazepine Peripheral neuropathy, hepatitis Pyrazinamide Good meningeal penetration Liver toxicity, arthralgia, (for TB meningitis) gout Optic neuritis, leading to impaired colour vision, Use TB (treatment and prophylaxis) TB Ethambutol Renal excretion – reduce dose in renal failure scotomata and reduced TB and other visual acuity (check baseline mycobacteria vision and monitor on treatment) Steroids in TB treatment The addition of glucocorticoids is currently recommended for meningeal and pericardial TB. BCG immunisation BCG immunisation contains live, attenuated Mycobacterium bovis. UK BCG policy no longer recommends immunisation at age 10–14; since 2005, the policy is targeted immunisation of high-risk individuals. Those for whom BCG is recommended include: • • • • • Neonates born in, or with parents or grandparents from, an area with TB notification rates ≥40/100 000 per year Neonates with a recent family history of TB Mantoux-negative (tuberculin skin test) close contacts of those with active TB Mantoux-negative new entrants to the UK, aged >16, from an area with notification rates ≥40/100 000 Unvaccinated, Mantoux-negative individuals at occupational risk (eg health-care workers). BCG is contraindicated in: • Immunocompromised individuals, eg receiving oral steroid treatment, HIV infection, haematological malignancies. 11.6.2 Non-tuberculous mycobacteria Also called opportunistic atypical or ‘mycobacteria other than tuberculosis’ (MOTT), this group includes mycobacteria other than M. tuberculosis complex (which includes M. tuberculosis, M. africanum and M. bovis). Some clinical associations of the more common opportunistic mycobacteria are given in Table 11.10. Diagnosis UK guidelines for management of these infections give guidance on assessing the significance of a laboratory isolate, depending on the sample from which it is cultured, the number of isolates, degree of growth and the patient’s clinical condition. Those with established, chronic lung disease, such as emphysema, bronchitis or cavitation from previous TB, are at increased risk of opportunistic mycobacterial disease, as are immunocompromised individuals, eg those with HIV infection. Pulmonary disease is diagnosed when two specimens, at least 7 days apart, are isolated from a patient whose chest radiograph is consistent with mycobacterial disease, with or without symptoms or signs. Table 11.10 Clinical associations of more common opportunistic mycobacteria M. kansasii M. malmoense Pulmonary disease resembling tuberculosis M. avium complex M. xenopi M. fortuitum Lymphadenitis M. avium complex M. malmoense M. scrofulaceum Cutaneous disease M. marinum (fish-tank granuloma) M. ulcerans (Buruli ulcer) M. fortuitum Disseminated disease M. avium complex (particularly in advanced HIV infection) M. kansasii Treatment Treatment is with combinations of antimycobacterial drugs, depending on the site of disease, HIV status of the patient and the organism isolated. Treatment regimens are longer than for TB, and may be up to 2 years or longer if a patient remains immunosuppressed or continues to have positive cultures. Mycobacterium avium complex This subgroup of opportunistic mycobacteria includes M. avium, M. intracellulare and a few other minor species, but is usually referred to as ‘MAC’ or MAI (Mycobacterium avium intracellulare). These are ubiquitous environmental organisms and are not acquired by person-to-person spread. In immunocompetent people, MAC can cause pulmonary infection in one of two patterns: 1. Disease resembling tuberculosis in elderly smokers with chronic lung disease Nodular infiltrates and a bronchiectasis-like pattern in those without chronic lung disease (‘Lady 2. Windermere syndrome’), with a productive cough but no systemic symptoms. Paediatric infection can cause lymphadenopathy. Since the start of the HIV pandemic, MAC is commonly seen in HIV-infected individuals with low CD4 counts. It causes systemic symptoms, fever and sweats. A full blood count may show pancytopenia. It can be cultured from blood or bone marrow in addition to sputum and stool. Consideration of primary prophylaxis with azithromycin is recommended for those with a CD4 count <50 cells/mm3 until the CD4 count is improved by antiretroviral therapy. MAC is treated using combinations of anti-mycobacterial drugs as above. Mycobacterium leprae For Mycobacterium leprae, see Section 11.7.5. 11.7 SPECIFIC TROPICAL INFECTIONS This is not a comprehensive review of tropical medicine and more extensive information on a greater range of illnesses can be sought by those interested. However, the main differentials, focusing on those most likely to appear in membership exams, and most important imported infections are included here. 11.7.1 Malaria Four Plasmodium species commonly affect humans: Plasmodium falciparum, P. vivax, P. ovale and P. malariae (A fifth of P. knowlesi is increasingly recognised as a human infection in south-east Asia). P. falciparum is the only one of these four commonly to cause severe disease, and therefore the majority of deaths. All are transmitted by female anopheles mosquitoes, which require blood for the development of their eggs, and all can be transmitted by blood transfusion. Worldwide, the majority of malaria mortality is in sub-Saharan Africa, but it occurs throughout the tropics. IPs vary between species: for P. falciparum it is usually 7–14 days, but may be longer. IPs are longer for other species. Diagnosis Thick-film examination (higher sensitivity), then thin-film examination (to determine species and, if P. falciparum, parasitaemia). Trophozoites are the form seen on blood films, inside red cells. Schizonts seen on a film are a marker of severity. Antigen tests are used in most labs and can differentiate between species. Repeat films are required if negative and there is a high clinical suspicion. Falciparum malaria Falciparum malaria is defined as severe if the parasitaemia (percentage of red cells on a thin film that contain malaria parasites) is 2% or more, or if there are complications (evidence of multisystem involvement, as below). Clinical features Clinical features are fever, headache, rigors, myalgia and thrombocytopenia (common in non-severe malaria). It may present with gastrointestinal symptoms and commonly presents with jaundice, which is mostly pre-hepatic, due to haemolysis (the jaundice often leads to initial misdiagnosis as acute hepatitis, a potential trap in clinical practice and MRCP questions). It may be complicated by: • • • • • Cerebral malaria: reduced level of consciousness (strictly defined as ‘coma’), seizures, focal neurological disorders, but not meningism Renal failure: which may be severe and require haemodialysis, with blackwater fever or haemoglobinuria due to haemolysis Pulmonary oedema and acute respiratory distress syndrome (ARDS): It is vital not to overload with fluid Severe anaemia: due to haemolysis and bone marrow suppression, particularly in children Hypoglycaemia: regular glucose monitoring is important, particularly as quinine can also cause hypoglycaemia • Algid malaria: malaria complicated by sepsis due to infection with Gram-negative organisms • Coagulopathy: in addition to thrombocytopenia Hyperreactive malarial splenomegaly (‘tropical splenomegaly syndrome’): massive • splenomegaly secondary to malaria, which may resolve with continuing antimalarial therapy. Treatment Artesunate is the most effective therapy for severe falciparum malaria, used intravenously. Quinine may still be used, intravenously for severe and oral for non-severe falciparum, for 5 days or until blood films are negative. This must be followed by a second agent: doxycycline 200 mg daily for 7 days, is preferable to Fansidar (pyrimethamine and sulfadoxine) single dose. Chloroquine is no longer recommended for falciparum malaria due to widespread resistance. Benign malaria P. vivax, P. ovale and P. malariae present with symptoms similar to falciparum malaria, but lack the complications or high parasitaemia. Most West Africans are protected against P. vivax by lack of the Duffy antigen, the receptor via which the merozoite stage of the parasite gains entry to red blood cells. The survival advantage conferred by the lack of this antigen accounts for the widespread absence of P. vivax in this region. Treatment is with oral chloroquine, followed with primaquine for 14 days to eliminate liver hypnozoites in P. vivax and P. ovale (but not P. malariae). Before giving primaquine, glucose-6-phosphatase dehydrogenase (G6PD) deficiency and pregnancy should be excluded. Primaquine can cause severe haemolysis in those G6PD deficiency; if it is required, then dose-and-interval adjustments can be made to avoid haemolysis. Prophylaxis against malaria Drugs used for prophylaxis of malaria when travelling to endemic areas include: doxycycline, mefloquine, Malarone (atovaquone and proguanil), and chloroquine and proguanil. The latter is not recommended for travel to sub-Saharan Africa due to resistance. Bite prevention, including use of insect repellents and bed nets, is an essential part of risk reduction. 11.7.2 Enteric fever (‘typhoid’) Enteric fever is caused by Salmonella typhi and S. paratyphi, and is common in travellers returning from Asia, with around 350 cases per year reported in the UK, most associated with travel to the Indian subcontinent. Incubation period The IP is 1–3 weeks, depending on inoculating dose. Transmission Transmission is by ingestion of contaminated food or water. Enteric fever is endemic in areas with poor sanitation. Risk is increased with gastric acid suppression. Clinical features Enteric fever is a syndrome of fever, myalgia, cough, constipation, abdominal pain and headache. Features worsen with time and peak in the third week. Deafness and diarrhoea can occur and there is a classically described ‘relative bradycardia’. Hepatosplenomegaly and ‘rose spots’ (pale pink, blanching spots on the trunk) may be found. Complications include psychosis or altered mental state, hepatitis, cholecystitis, pneumonia, pericarditis and meningitis. Leukopenia is typical. Untreated, mortality is from septicaemia or gastrointestinal perforation. Diagnosis Diagnosis is made by culture of the organism, a Gram-negative bacillus, from blood, bone marrow, stool or urine. Serology/Widal test is not useful. Treatment Prompt antibiotic therapy reduces mortality. Fluoroquinolones (eg ciprofloxacin) are the most effective treatment if the organism is susceptible, but there is widespread resistance in Asia and azithromycin is preferred for uncomplicated disease in those with recent travel to Asia. Intravenous ceftriaxone is an alternative for more severe disease. Treatment is for 14 days. Relapse is relatively common and the organism can persist in the gallbladder. Chronic secretion of the organism occurs occasionally and such individuals can transmit to others. Immunisation Polysaccharide vaccine is given intramuscularly; protection (S. typhi but not S. paratyphi) is incomplete and lasts for 3 years (alternatives are oral live, attenuated or killed whole-cell injectable vaccines). It is recommended for travellers to endemic areas. 11.7.3 Amoebiasis The protozoon Entamoeba histolytica is transmitted by ingestion of food or water contaminated by amoebic cysts secreted in the faeces of asymptomatic individuals. It is found wherever sanitation is poor. Amoebae multiply in the gut and can cause invasive colitis and amoebic dysentery or amoebic liver abscess (containing ‘anchovy sauce’ pus), which if untreated can discharge into a cavity such as the peritoneum, pleural cavity or pericardium. It can also cause extraintestinal disease, eg abscesses in the lung or brain. The IP can be as long as several months. Clinical features Amoebic dysentery with blood and mucus in stools. Amoebic liver abscess can cause right upper quadrant pain and tenderness, right shoulder tip pain, with fever and leukocytosis. There may be hepatomegaly or signs of rupture of the abscess into a cavity, such as peritonitis or pericardial effusion. Diagnosis Amoebic trophozoites seen on microscopy of fresh stool, though repeat specimens may be required as sensitivity is poor. Aspirates from abscesses may also be examined for trophozoites. Serology is used for invasive disease and imaging is useful Treatment Metronidazole with diloxanide furoate to eradicate intestinal cyst carriage. Aspiration of abscess if large or causing severe pain or swelling. 11.7.4 Schistosomiasis (‘bilharzia’) These trematode, or blood fluke, infections cause much mortality and morbidity worldwide. Schistosomiasis is most common in Africa, particularly in freshwater lakes, and in the Middle East. The three main species affecting humans are S. mansoni (Africa, South America); S. haematobium (principally Africa, particularly the Nile valley) and S. japonicum (east Asia). Transmission to humans occurs by exposure to fresh water infested with larvae (cercariae) from infected snails. The cercariae penetrate the skin and migrate as developing worms towards the venous plexus of the bladder or mesenteries, depending on the species, where they remain as adult pairs and lay eggs, which are in turn passed in the urine or faeces. Principal organs affected are: • S. haematobium (urinary tract) S. mansoni and S. japonicum (bowel and liver), although CNS, pulmonary and other sites can • become involved. Clinical features Acute: cercarial dermatitis (‘swimmers’ itch’) is an acute reaction to cercarial penetration, causing a self-limiting, pruritic, papular rash, within 24 hours of freshwater exposure. Katayama fever, or acute schistosomiasis, is less common but more severe and develops between 4 and 8 • weeks after exposure, when the first eggs are produced. Features of an immune complexmediated syndrome may include fever, urticaria, eosinophilia, diarrhoea, hepatosplenomegaly, cough and wheeze Chronic: the large numbers of eggs produced by adult worms are the cause of pathology in • chronic schistosomiasis. The eggs cause granulomatous reactions and fibrosis in affected organs, leading to pathology as follows: Urinary tract: haematuria (‘terminal haematuria’) as eggs pass through the bladder epithelium, fibrosis and calcification of the bladder (visible on plain radiograph), obstructive • uropathy and, usually after at least 20 years of infection, squamous cell carcinoma of the bladder Bowel and liver: haemorrhagic polyps and colitis, hepatomegaly, periportal fibrosis causing • portal hypertension (with splenomegaly, varices and ascites) Other sites: eggs can transit via the pulmonary and systemic circulation to cause pathology in other organs, such as pulmonary hypertension (eg S. haematobium), paraparesis (from • transverse myelitis, eg S. mansoni), or seizures due to space-occupying lesions or encephalopathy (eg S. japonicum) Diagnosis Microscopic identification of eggs in the urine (terminal urine sample) or faeces, or in a tissue biopsy. Serological diagnosis is useful and would usually (but not always) be positive in Katayama fever. Treatment Praziquantel with steroids and anticonvulsants for CNS disease. 11.7.5 Leprosy Leprosy (Hansen’s disease) is caused by the slowgrowing, intracellular, acid-fast bacillus Mycobacterium leprae, which is transmitted person-to-person by respiratory droplets from the nasal mucosa. It is associated with overcrowding and poverty, and most cases are found in south Asia (more than in Africa and South America). Unlike TB, the risk of developing leprosy is not greatly increased by HIV infection. BCG offers some protection. Incubation period The IP is 2–12 years (shorter for tuberculoid leprosy, longer for lepromatous leprosy). Of those who are infected, 95% develop an effective immune response and clear the organism; others develop disease. Clinical features The organism grows well at lower temperatures and thus affects the skin, upper respiratory mucosa, superficial nerves, anterior chamber of the eye, lymph nodes and testes. Features are depigmented, anaesthetic skin patches or other, sometimes nodular, skin lesions, thickened superficial nerves (eg ulnar nerve), or signs of involvement of other organs, such as visual impairment. There is a spectrum of disease from tuberculoid (paucibacillary) to lepromatous (multibacillary) types, depending on the degree of the T-cell-mediated immune response to the organism, as shown in Table 11.11. Diagnosis Diagnosis is based on the clinical features in a patient from an area where leprosy is endemic, plus a skin smear from a lesion, stained for mycobacteria. M. leprae cannot be grown in vitro. Treatment The World Health Organization recommends combination drug treatment of rifampicin, dapsone and clofazimine for 12 months for multibacillary leprosy, and rifampicin and dapsone for 6 months for paucibacillary leprosy. Clofazimine can cause abnormal skin pigmentation and ichthyosis. Other aspects of care, such as protection of anaesthetic feet and hands, are also important. Reactions These are due to a shift in the individual’s immune response, usually during treatment, either up or down the spectrum. Reversal reaction (type 1) Erythematous skin lesions and nerve damage with pain and loss of function occur in patients with delayed-type hypersensitivity and an increasing cell-mediated immune response to M. leprae. Prednisolone treatment can reduce nerve damage. Erythema nodosum leprosum (type 2) This occurs in patients at the lepromatous end of the spectrum. Reactions comprise fever, erythema nodosum leprosum (ENL) and occasionally life-threatening glomerulonephritis and renal failure due to immune complex deposition. Chronic or severe ENL can lead to amyloidosis. Treatment is with prednisolone or, in chronic reactions, higher-dose clofazimine or thalidomide. 11.7.6 Lymphatic filariasis Filarial worm larvae, most commonly Wuchereria bancrofti or Brugia malayi, are transmitted throughout the tropics by mosquitoes and cause debilitating deformities of the limbs as a result of lymphatic damage. This can lead to ‘elephantiasis’ of the limbs. Microfilariae produced by adult worms can cause tropical pulmonary eosinophilia. Diagnosis Diagnosis is made by clinical appearance, microfilariae on blood film, serology and the presence of an eosinophilia. Treatment Diethylcarbamazine (DEC) and supportive treatment for lymphoedema. Table 11.11 Spectrum of disease in leprosy 11.7.7 Filariasis, including onchocerciasis Onchocerciasis (‘river blindness’) is a form of filariasis caused by Onchocerca volvulus and transmitted by simulium black flies. It occurs mainly in west and central Africa (but also in south and central America) near fast-flowing rivers. Clinical features include: subcutaneous nodules containing adult worms (onchocercomas); thickened, itchy, inelastic, wrinkled skin with lymphoedema, leading to ‘hanging groin’; and eye lesions leading to blindness. Eye lesions involve the cornea, anterior chamber and iris. Diagnosis Skin snips to detect microfilariae are the gold standard, but not widely available. Serological tests are more commonly used outside specialist centres. Treatment Ivermectin, single dose, is used in the treatment of individuals and in mass eradication campaigns in Africa. 11.7.8 Cysticercosis The pork tapeworm Taenia solium differs from the beef tapeworm, T. saginata, in that it can cause invasive disease in the human host. Intestinal infection with adult tapeworms is caused by ingestion of larval cysts in undercooked pork. In addition, ingestion of eggs from faecal–oral contamination can cause migration of the parasite to the tissues, most notably the muscles and CNS. Neurocysticercosis is a common cause of epilepsy worldwide. Clinical features Calcified subcutaneous or muscle cysts, visible on radiograph; epilepsy or spinal symptoms from CNS lesions. Diagnosis Diagnosis is made by imaging and serology for cysticercosis (eggs on stool microscopy for intestinal tapeworm infection). Treatment Albendazole or other anthelmintic drugs for intestinal tapeworm infection. Neurocysticercosis may require anticonvulsants and steroids before using anthelmintic drugs. 11.7.9 Trypanosomiasis African trypanosomiasis Trypanosoma brucei spp. (gambiense [West Africa] and rhodesiense [East Africa]) are transmitted by tsetse flies and cause sleeping sickness, which occurs in sub-Saharan Africa. In the first stage, trypanosomes multiply in blood and lymphatic tissues, producing fever, headaches, joint pains and itching. Later, trypanosomes invade the CNS from the blood and cause a meningoencephalitis, ultimately causing death in weeks or up to years, depending on the subtype. It is rarely seen in the UK, although imported cases are usually associated with travel to national parks in Africa. Diagnosis Trypanosomes seen on blood or CSF microscopy; serology. Treatment The WHO recommends treatment of the first stage with pentamidine (W. African) or suramin (E. African), and the second stage with nifurtimox plus eflornithine (W. African) or the toxic arsenical compound melarsoprol (E. African) South American trypanosomiasis Trypanosoma cruzi is transmitted by reduviid bugs and causes Chagas’ disease, which occurs in Central and South America. It can also be transmitted by blood transfusion. Clinical features Acute infection gives non-specific symptoms. Chronic complications include megaoesophagus, megacolon and cardiomyopathy with arrhythmias. Diagnosis Serology, or trypanosomes seen on blood films. Treatment Benznidazole or nifurtimox. Surgery for gastrointestinal complications or symptomatic treatment for cardiac disease. Note on eosinophilia In parasitic infections, eosinophilia is related to the tissue-migration phase of the life cycle of a multicellular parasite. It therefore occurs in schistosomiasis, strongyloidiasis and filariasis, but not in malaria, amoebiasis or giardiasis. Also note the non-infective causes of eosinophilia, including some malignancies and connective tissue diseases, drug reactions and allergies 11.7.10 Leishmaniasis The many species of unicellular, protozoan leishmania parasites, transmitted by sandflies from animal reservoirs, cause cutaneous, mucocutaneous and visceral (kala-azar) leishmaniasis. Cutaneous leishmaniasis occurs mostly in central and south Asia and South America, and is relatively common in returning travellers in the UK. Visceral leishmaniasis occurs mostly in south Asia, Brazil and north-east Africa, but is rarely seen in travellers from the UK; there is an association with HIV infection. Cutaneous leishmaniasis: skin lesions, including ulcers, nodules or plaques, with local lymphadenopathy, occur weeks to months after exposure. Diagnosis is by biopsy of lesions with appropriate staining to visualise the amastigote stage of the parasite and culture if available. Treatment is with sodium stilbogluconate. Mucocutaneous leishmaniasis: certain Leishmania spp. cause a destructive mucosal lesion, often at the mucocutaneous junction of the nose, with secondary bacterial infection. Diagnosis is by biopsy of the edge of a lesion for histological examination. Treatment is with sodium stilbogluconate as for cutaneous disease. Visceral leishmaniasis (kala-azar): a systemic illness with fever, weight loss, hepatosplenomegaly and, in some cases, bone marrow involvement, with cytopenias. Diagnosis is by biopsy of lesions, lymph nodes, bone marrow or, where appropriate skills are available, spleen. Treatment is with liposomal amphotericin B and prognosis is very poor if untreated, particularly in those with HIV coinfection. 11.7.11 Hookworm Ancylostoma duodenale and Necator americanus are helminths, transmitted by penetration of larvae in the soil through the skin. Infection is common where sanitation is poor, and hookworm is a common cause of anaemia worldwide. The worms mature in the intestines then attach to the mucosal surface, causing bleeding and iron-deficiency anaemia. Diagnosis Characteristic eggs are seen on stool microscopy. Treatment Anthelmintic drugs, such as mebendazole. 11.7.12 Strongyloidiasis An intestinal helminth found throughout the tropics and subtropics, S. stercoralis has a life cycle that can be completed entirely within the human host and therefore cause illness many years after original exposure. Primarily an intestinal disease (diarrhoea, eosinophilia) with cutaneous manifestations (larva currens), in the context of immunosuppression, usually with steroids, can lead to a hyperinfection syndrome with widespread larvae included in respiratory secretions and disseminated disease with Gram-negative sepsis and organ failure. Strongyloides spp. are associated with human T-cell lymphotrophic virus-1 (HTLV-1) infection. Diagnosis Larvae seen in stools (or elsewhere in hyperinfection syndromes), or serology. Treatment Ivermectin or albendazole. 11.7.13 Dengue fever Dengue fever is caused by a mosquito-borne flavivirus prevalent throughout the tropics, with greater risk in south-east Asia and the Caribbean. The IP is 5–8 days and symptoms are fever, rigors, headache (characteristically retro-orbital pain), with blanching, maculopapular rash and lymphadenopathy. There may be leukopenia, thrombocytopenia and mild transaminitis. The illness is usually mild and self-limiting. Dengue haemorrhagic fever is thought to result from subsequent infection with a second of the four serotypes Diagnosis In practice, the diagnosis is clinical in the context of the travel history. Serology confirms, but results take time. Treatment No specific treatment is available: supportive measures only. Mild disease is self-limiting, but there is substantial mortality in Dengue haemorrhagic fever (rare in the UK). 11.7.14 Viral haemorrhagic fevers The main viruses of relevance here, to consider in returning travellers to the UK from Africa, are the arenavirus, Lassa, and the filoviruses, Marburg and Ebola. Crimean-Congo haemorrhagic fever is more widespread geographically, occurring in Africa, but also parts of the Middle East, Asia and Europe. These viruses can transmit person-to-person via blood and body fluids, including indirectly via contamination of the environment, and isolation measures for suspected cases are essential to protect health-care workers. Case fatality rates are high. Viral haemorrhagic fevers (Lassa, Ebola, Marburg) should be considered in returning travellers with fever developing within 21 days of visiting endemic countries in west and central Africa, particularly if they have visited rural areas. A risk assessment should be undertaken and special isolation procedures are required for suspected cases and their blood specimens until a viral haemorrhagic fever is excluded. Malaria is an important and much more common differential diagnosis, and imported viral haemorrhagic fevers are very rare. Management of suspected cases should be in collaboration with public health. Those with confirmed disease should be managed at a high-security infectious disease unit. Other viruses (including those causing dengue fever, Chikungunya and yellow fever) can have haemorrhagic manifestations, but most are less severe and do not transmit person-to-person, so are not managed in the same way. Diagnosis A malaria film would usually be done to exclude malaria before moving on to testing for viral haemorrhagic fever. Diagnostic tests are by serology or PCR at a national reference laboratory. All specimens need to be handled in collaboration with the local laboratory to reduce risk to laboratory staff. Treatment Ribavirin is recommended for confirmed Lassa fever. No specific antivirals are effective for Ebola or Marburg. 11.7.15 Rickettsial infections African tick-bite fever typhus (R. africae) is the main rickettsial infection to consider in returning travellers, particularly from Africa (others include Rocky Mountain spotted fever, Mediterranean spotted fever and scrub typhus [ O. tsutsugamushi] in Asia). Travel to game parks in southern Africa is a particular risk factor for R. africae. IP is 5–14 days and symptoms are non-specific, with fever, headache and myalgia. An eschar may be present at the site of a tick bite, with local lymphadenopathy, maculopapular rash and conjunctival infection. Diagnosis Serology. Treatment Doxycycline. 11.7.16 Approach to fever in the returning traveller Priorities when assessing a returning traveller are to detect and treat potentially life-threatening conditions, and to consider and manage infection control issues. A thorough travel history is essential, including destinations visited before the most recent travel, whether rural or urban setting, and activities undertaken. Details of pre-travel immunisations and malaria prophylaxis used are required. Viral haemorrhagic fever must be considered initially in travellers returning from endemic areas with symptom onset within 21 days of leaving. Examination will give an indication as to the focus of fever. Initial investigations (having excluded viral haemorrhagic fever) include malaria film, blood count, biochemistry, blood culture, urinalysis and chest radiograph. Serological tests can be done for specific infections thought likely. Returning travellers would normally be isolated for infection control reasons until a diagnosis has been made. The main important differentials in those returning from sub-Saharan Africa are viral haemorrhagic fever, malaria, rickettsial infections and HIV (including primary HIV infection/seroconversion). From Asia, they are malaria, enteric fever, dengue fever and HIV. In many returning travellers, a specific diagnosis is not made. Alternatively, a non-infectious diagnosis or one unrelated to the recent travel may be the cause of fever. 11.8 IMPORTANT ZOONOSES 11.8.1 Brucellosis Brucella spp. (B. abortus from cattle, B. melitensis from goats or sheep, B. suis from pigs) are Gram-negative coccobacilli that can cause disease if humans come into contact by handling animal carcasses, ingesting unpasteurised milk or inhaling aerosols from infected animal carcasses or laboratory isolates. The majority of UK cases are acquired abroad. The organisms spread through the blood and lymphatics, and localise in the reticuloendothelial system, causing granulomas. It is most common in Mediterranean and Middle Eastern countries and South America, and rare in the UK. Clinical features The IP may be 5–60 days and presenting features include fever, malaise, sweats and weight loss. Hepatosplenomegaly and lymphadenopathy may be present. Less commonly there is arthritis, osteomyelitis, orchitis, meningoencephalitis, endocarditis or granulomatous hepatitis. The acute phase may be followed by a relapsing–remitting course (‘undulant fever’). Diagnosis The organism may be grown in prolonged culture of blood or bone marrow. Serology is an alternative and more commonly positive than cultures. Treatment Doxycycline and rifampicin or, if more severe, then intravenous aminoglycosides. Treatment is for 3– 6 weeks. 11.8.2 Lyme disease Lyme disease is caused by the spirochaete Borrelia burgdorferi, transmitted by hard ticks (ixodid ticks) from an animal reservoir. It is found in large parts of Europe, including the UK (forest areas) and the USA (north-east), China, Japan and Australia. Clinical features Early features (with variable IP of a few days to a month) include a characteristic rash at the site of the tick bite, called erythema migrans, which is an expanding erythematous plaque with central clearing. There may be local lymphadenopathy and fever. Later features (weeks to months later) follow direct or haematogenous dissemination and may include focal neurological symptoms (eg Bell’s palsy), encephalitis, meningitis, cardiac involvement with atrioventricular block, or arthritis with effusion. Around 90% present with erythema migrans and 10% with other features, including neuroborreliosis and arthritis. Diagnosis Serology (most positive after 4 weeks) in an accredited laboratory, or PCR of CSF, synovial fluid or tissue. CSF is lymphocytic in Lyme meningitis. Treatment Doxycycline or erythromycin for erythema migrans, which can be treated without serological confirmation. Intravenous ceftriaxone for neurological or cardiac manifestations. 11.8.3 Q fever Q fever refers to syndromes caused by infection with the rickettsial organism, Coxiella burnetii. It is usually transmitted by exposure to cattle or sheep, by aerosol or direct contact, or from contaminated milk. It occurs worldwide. Clinical features Fever, pneumonia or hepatitis. A few individuals suffer a chronic infection with ‘culture-negative’ endocarditis and possibly myocarditis. Other features or less common presentations include rash, arthralgia, meningoencephalitis and glomerulonephritis. Diagnosis Acute and convalescent serology. Treatment Tetracyclines for 2–3 weeks. Longer, combination therapy is required for cardiac involvement. 11.8.4 Toxoplasmosis Toxoplasma gondii is a common parasite infection in Europe, with adult parasite forms in the cat. The life cycle involves humans by ingestion of oocysts from food contaminated with cat faeces or consumption of undercooked meat (eg beef, pork). Clinical features Primary toxoplasmosis infection can be asymptomatic or manifest as an infectious mononucleosis-like illness, with fever, lymphadenopathy, myalgia and fatigue. Reactivation in the context of immunosuppression, especially HIV with low CD4 count, can cause intracerebral lesions resulting in focal neurology and an encephalitis. Primary infection during early pregnancy has severe sequelae for a minority, with fetal retinochoroiditis, encephalomyelitis, and hydrocephalus or microcephaly. With infection in later pregnancy, most infants develop retinochoroiditis in infancy, having been normal at birth. Diagnosis Serology (IgG represents previous exposure and IgM acute infection) and/or PCR on appropriate specimens. Treatment No specific treatment for primary infection in immunocompetent individuals. Pyrimethamine, sulfadiazine and folinic acid for reactivation diseases in immunocompromised individuals. Spiramycin is sometimes used for suspected infection in pregnancy to reduce the risk of transmission to the fetus. Chapter 12 Maternal Medicine CONTENTS 12.1 Physiology of normal pregnancy 12.1.1 Cardiovascular system 12.1.2 Respiratory system 12.1.3 Haematological system 12.1.4 Renal system 12.2 Pharmacokinetics in pregnancy 12.3 Pre-existing medical disorders and pregnancy 12.3.1 Diabetes and pregnancy 12.3.2 Cardiac disease and pregnancy 12.3.3 Renal disease and hypertension in pregnancy 12.3.4 Antiphospholipid syndrome and pregnancy 12.3.5 Thyroid disease and pregnancy 12.3.6 Epilepsy and pregnancy 12.4 Medical complications of pregnancy 12.4.1 Hypertensive disorders of pregnancy 12.4.2 Thrombotic complications in pregnancy Maternal Medicine 12.1 PHYSIOLOGY OF NORMAL PREGNANCY Pregnancy impacts upon every system in the body, and each system adapts in order to accommodate the demands of the fetoplacental unit. Consequently, pregnancy can adversely affect many preexisting medical conditions and, likewise, many pregnancy complications arise because physiological adaptation does not occur. 12.1.1 • • • • • • • • • Cardiovascular system There is an increase in plasma volume from 2600 mL to approximately 3800 mL, reaching a plateau by 32 weeks’ gestation Cardiac output rises by about 40%, from about 4.5 L/min to 6 L/min, reaching a plateau by 24– 30 weeks’ gestation. This occurs because of an increase in heart rate (from approximately 80 beats/min to 90 beats/min) and an increase in stroke volume Left ventricular hypertrophy and dilatation facilitate this change in cardiac output but contractility remains unchanged. The structural changes revert to normal early post-partum and definitely by 6 weeks Together with the upward displacement of the diaphragm, the apex of the heart is moved anterior and to the left These changes may result in ECG findings of left axis deviation, depressed ST segments and inversion or flattening of the T wave in lead III Echocardiogram may show a small pericardial effusion and mild valvular regurgitation. The valvular regurgitation is a reflection of dilatation There is a decrease in total peripheral resistance that outstrips the increase in cardiac output, and this results in a fall in blood pressure (between 8 and 36 weeks’ gestation). This generalised vasodilatation accommodates the increased blood flow to the uterus and other organs. A nadir in diastolic BP is typically seen at about 16 weeks’ gestation, coincident with second-wave spiral artery dilatation Symptoms of pregnancy may mimic cardiac disease, such that dyspnoea, peripheral oedema and palpitations are all common complaints in normal pregnancy A benign ejection systolic murmur occurs in 96% of pregnant women – due to increased blood volume and flow, together with anaemia. 12.1.2 Respiratory system Vital capacity does not change during pregnancy but the tidal volume expands into the expiratory and inspiratory reserve volume. Consequently, ventilation increases by 40% in pregnancy. This increase in ventilation exceeds the increase in oxygen consumption and there is a proportional fall in PCO2. The bicarbonate level falls to maintain a normal pH and there is a concomitant fall in sodium. 12.1.3 Haematological system • There is an increase in red cell mass, from a non-pregnant level of 1400 mL to 1650–1800 mL Plasma volume increases proportionately more than red cell mass, resulting in a fall in the • haematocrit and haemoglobin concentration in normal pregnancy, such that a haemoglobin level of 1.05 g/L may be within ‘normal’ limits and represents a physiological anaemia There is an increased demand for iron, mainly to meet the demands of the increased red cell • mass and to a lesser extent the requirements of the developing fetus and placenta. This demand is not quite matched by an increase in dietary absorption There are increases in the levels of factors VII, VIII and X, and in the level of plasma fibrinogen, • such that in late pregnancy the fibrinogen concentration is at least double that in the non-pregnant state 9 • White blood cell count increases and may peak at >20 × 10 /L in stressful conditions such as labour. This can make the diagnosis of infection difficult in pregnancy • A decrease in platelet concentration to around 100–150 × 109/L can also be seen. 12.1.4 Renal system • Kidneys increase in length by about 1 cm in pregnancy Ureters become dilated, secondary to increased progesterone and to the obstructive effect of the • gravid uterus Renal blood flow increases from about 1.2 L/ min in the non-pregnant state to at least 1.5 L/ min • in pregnancy. This results in an increase in glomerular filtration rate (GFR) Increased GFR leads to a fall in blood urea (from 4.3 mmol/L to 3.1 mmol/L) and creatinine • (from 73 μmol/L to 47 μmol/L) Increased GFR also increases the filtered load of glucose and benign glycosuria is common in • pregnancy. 12.2 PHARMACOKINETICS IN PREGNANCY The physiological changes of normal pregnancy profoundly affect pharmacokinetics. Physiological changes in pregnancy which affect drug pharmacokinetics • Renal blood flow increases and leads to increased renal clearance Increased plasma volume and fluid retention lead to an increased volume of distribution and • decreased plasma concentration Induction of liver enzyme pathways increases the hepatic metabolism of certain drugs and results • in a decreased plasma concentration The concept of placental transfer is unique to pregnancy. Essentially, every drug (with the exception of heparin) crosses the placenta and has the potential to cause unwanted side-effects, including teratogenic effects in the unborn fetus. Under most circumstances, drugs cross the placenta and will equilibrate between the fetal and maternal compartments. In view of this, drug therapy is best avoided unless absolutely necessary during the period of organogenesis in the first trimester (ie between conception and 12 weeks). If unavoidable, older drugs with established safety data should be the agents of first choice. Specific drugs are discussed in more detail later in this chapter. 12.3 PRE-EXISTING MEDICAL DISORDERS AND PREGNANCY 12.3.1 Diabetes and pregnancy Before the advent of insulin, women with type 1 diabetes who survived to the age of reproduction and were then able to become pregnant had a less than 50% chance of having a successful pregnancy. Today maternal mortality is rare, but both fetal and neonatal morbidity and mortality remain higher compared with the general pregnant population. Terminology and definitions Pregnancy induces profound metabolic alterations. To maintain stable concentrations of plasma glucose, insulin secretion must double from the end of the first to the third trimester. In pregnancy, glucose concentrations: • Increase postprandially • Decrease with fasting • Decrease with gestation. Pregnancy is associated with insulin resistance. This is a post-receptor defect, mediated by an increase in pregnancy-associated hormones and cortisol. Changes in insulin also cause accelerated starvation, with an increase in triglyceride breakdown resulting in raised free fatty acids and ketone bodies. The diagnosis of diabetes in pregnancy is based on a 75-g oral glucose tolerance test (GTT) (Table 12.1). Women with gestational diabetes mellitus (GDM) are those who are found, during pregnancy, to have a GTT that meets the threshold for diagnosing diabetes (Table 12.1). A small proportion of these women will inevitably have true, previously undiagnosed, diabetes. With regard to the diagnostic thresholds for GDM, The NICE (National Institute for Health and Care Excellence) guidelines are not evidence based and never have been. The guidelines are currently being revised by NICE and will be out in the next 2 years. Table 12.1 Interpreting the oral glucose tolerance test in pregnancy Diagnosis Fasting blood glucose (mmol/L) Two-hour blood glucose (mmol/L) Diabetes ≥5.1 ≥8.5 Impaired glucose tolerance not diagnosed anymore. Diagnostic thresholds vary significantly around the country. The IADPSG (International Association of Diabetes in Pregnancy Study Groups) and the WHO (World Health Organization) have recently recommended ≥5.1 mmol/L (fasting) or 8.5 (2-h post 75-g oral glucose load). This is based on an odds ratio (OR) of 1.75 for having a large-for-gestational age (LGA) baby from the HAPO (Hyperglycemia and Adverse Pregnancy Outcome) data. There is enormous debate nationally about the significant resource it would require to treat all these women as GDM. Risk factors for screening BMI >30 kg/m2 Previous macrosomic baby weighing ≥4.5 kg Previous gestational diabetes First-degree relative with diabetes Family origin with a high prevalence of diabetes (south Asian, black African–Caribbean and • Middle Eastern) • • • • Those with a previous history of gestational diabetes should be offered a GTT between 16 and 18 weeks’ gestation, repeated at 28 weeks’ gestation if earlier test normal. Women with an identifiable risk should be offered a GTT between 24 and 28 weeks’ gestation. Effects of diabetes on the fetus Congenital malformations Overall there is a 4- to 10-fold increase in the incidence of congenital abnormalities in infants of diabetic mothers compared with the normal pregnant population • Cardiac and neural tube defects are among the most common abnormalities Caudal regression: an embryological defect that occurs during the third week of intrauterine development and is strongly associated with maternal diabetes, although it is rare compared with • cardiac and neural tube defects. Although the syndrome is highly variable in severity, it can result in fusion of the lower limbs and urogenital and anorectal abnormalities • The exact mechanism underlying the increase in congenital abnormalities is unknown but may • reflect an abnormal metabolic environment (high serum glucose) around the time of organogenesis Fetal anomaly rates similar to those in the non-diabetic population can be achieved with • meticulous preconceptional glycaemic control. Spontaneous miscarriage Poorly controlled diabetes is associated with an increased risk of miscarriage, but women with moderately well-controlled diabetes have only a minimally increased risk A rate of miscarriage equivalent to that of the non-diabetic population can be achieved by • excellent glycaemic control. • Perinatal mortality In a multidisciplinary setting, excluding deaths from congenital malformations, perinatal mortality rates are similar between infants of diabetic mothers and those of normal pregnant women. Unexplained fetal death in utero Despite improvements in care, death in utero of a normally formed fetus still occurs. Conventional tests of fetal wellbeing have poor sensitivity for predicting such events. The aetiology of these deaths is complex but includes alterations in the following: Placental oxygen transfer (reduced red cell oxygen release mediated through 2,3• diphosphoglycerate [2,3-DPG]) Fetal acid: base balance (tendency towards metabolic acidosis, worsened by increasing maternal • glucose concentrations) • Organomegaly (results in increased metabolic demand) • Fetal thrombosis (more likely because of fetal polycythaemia). Effects of diabetes on the neonate Birthweight • • • • There is an increased incidence of both small-and large-for-gestational-age (SGA, LGA) fetuses born to diabetic mothers. SGA affects 2% of babies. It is increased in mothers with nephropathy (4.5%) and microalbuminuria (4%) Approximately 25–40% of infants of mothers with diabetes have birthweights >90th centile and as many as 35% have birthweights >95th centile. This leads to an increase in intrapartum complications, including an increase in both the caesarean section rate and the incidence of shoulder dystocia Increased growth rates may be seen as early as 20–24 weeks’ gestation Subcutaneous fat deposits correlate with maternal plasma glucose concentrations and glycated haemoglobin (HbA1c) levels, amniotic fluid C-peptide levels and fetal serum insulin/ glucose ratios • Fetal growth restriction is more frequently seen in diabetic women with long-standing disease and evidence of microvascular complications. Respiratory dysfunction Reduced phosphatidylglycerol production results in surfactant deficiency; this in turn predisposes the infant to hyaline membrane disease. Hypoglycaemia This arises because of the following: • Endogenous hyperinsulinaemia developed in utero • Reduced hepatic phosphorylase activity • Reduced glucagons and catecholamines resulting in reduced glucose release from the liver. Polycythaemia and jaundice Polycythaemia occurs in 29% of infants of diabetic mothers, compared with 6% of infants of normal pregnant women; there is a direct correlation with diabetic control. Polycythaemia results in an increased viscosity, which may cause the following: • Increased cardiac work Microvascular abnormality, leading to respiratory distress, renal vein thrombosis and necrotising • enterocolitis Jaundice occurs in about 19% of infants due to an increase in red cell destruction as well as • liver immaturity and poor handling of bilirubin. Hypocalcaemia and hypomagnesaemia Calcium and magnesium levels are lower in infants born to diabetic mothers, predisposing to neonatal seizures; the exact mechanism is unknown. Hypertrophic cardiomyopathy As many as 30% of infants may have an enlarged heart, and 10% of these may have associated cardiac dysfunction. This correlates with maternal diabetic control. The heart shows features similar to that of hypertrophic obstructive cardiomyopathy, but the dysfunction tends to resolve in the neonatal period. Management of pregnancy in the diabetic patient All patients should be counselled about the risks of pregnancy and the need for vigilant clinical management. Pregnancy should be planned. Pre-pregnancy • Switch to insulin if the patient is on oral hypoglycaemics unless on metformin (± glibenclamide) • Encourage tight glucose control (eg preprandial levels 3.5–5.9 mmol/L, postprandial <7.8 mmol/L) • Weight reduction if body mass index (BMI) >27 • HbA1c should be maintained at 48 mmol/mol (previously 6%) (Table 12.2) • Treat any retinopathy before rapid optimisation of glucose control Screen for nephropathy – if creatinine ≥125 μmol/L or estimated glomerular filtration rate (GFR) • <45 mL/h refer to nephrologist Stop angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and • statins • Start high-dose (5 mg) folic acid. Table 12.2 Glycated haemoglobin (HbA1c) levels DCCT: HbA1c (%) IFCC: HbA1c (mmol/mol) 6.0 6.5 7.0 7.5 8.0 9.0 42 48 53 58 64 75 DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry. Antenatal care It is very important to involve the multidisciplinary team in the care of the patient. Patients should be booked in the antenatal clinic at a very early stage with organisation of an ultrasound scan to accurately date the pregnancy (crown–rump length [CRL] at 8–12 weeks gives expected date of delivery (EDD) ± 5 days). Patients should be given dietary advice and baseline renal function should be assessed. Other important aspects of management include: • • • • • • Good glycaemic control reduces the risk of miscarriage, congenital malformations, stillbirth and neonatal death. Advise women to test fasting and 1-hour postprandial blood glucose levels after every meal during pregnancy. Maintain tight glucose control (preprandial levels 3.5–5.9 mmol/L); the patient should be warned about the possibility of hypoglycaemic episodes Serum screening should be interpreted with care as α-fetoprotein (AFP) and PAPPA (pregnancyassociated plasma protein A) levels are lower in diabetic pregnancies. Nuchal translucency (NT) screening (performed between 11 weeks 6 days and 13 weeks 6 days of gestation) is a more reliable alternative A detailed anomaly scan, including fetal echocardiography, should be performed Regular review with blood pressure measurement and urinalysis Referral to a nephrologist if serum creatinine is abnormal (≥120 μmol/L) or total protein excretion exceeds 2 g/day; thromboprophylaxis if proteinuria is >5 g/day Serial fetal growth and liquor volume assessment • Cardiotocograph (CTG) may be useful after 36 weeks to assess fetal wellbeing, in the light of possible risk of fetal death in utero In view of the increased risk of preterm delivery (induced or spontaneous) patients may require high-dose intramuscular fluorinated steroids (eg betamethasone 12 mg, two doses 12–24 h apart) to accelerate fetal lung maturation (by stimulating surfactant secretion). A sliding scale of insulin • would be necessary during this treatment. Tocolytics are used to stop uterine activity (ie in the treatment of preterm labour). Avoid ritodrine and salbutamol because these can interfere with glycaemic control. Alternatives are nifedipine and atosiban (an oxytocin receptor antagonist). The equivalent of the current DCCT HbA1c targets of 6.5% and 7.5% are therefore 48 mmol/mol and 58 mmol/mol in the new units, with the non-diabetic reference range of 4.0–6.0% being 20–42 mmol/mol. The timing and mode of delivery will be individualised according .to the patient and health of the fetus. Those with a normal size baby do not require induction of labour before term. Labour Good diabetic control should be maintained in labour (4–7 mmol/L). This will often necessitate the use of a sliding scale for insulin administration. The following are also important: • Continuous CTG Watch for obstructed labour and be aware of possible shoulder dystocia, both associated with • fetal macrosomia • High caesarean section rate (as high as 60–65%). Post-partum • Reduce insulin back to pre-pregnancy levels after delivery of the placenta • Encourage breastfeeding (safe with insulin, metformin and glibenclamide) • Discuss contraception (see below). Gestational diabetes/impaired glucose tolerance in pregnancy Initially, glycaemic control may be achieved through diet (total calories between 1800 and 2000/ day). Fibre intake should be increased and 50% of energy should be derived from carbohydrates. • • • • • If preprandial blood glucose levels are >6 mmol/L despite lifestyle and dietary changes, then therapy is required Regular insulin, the rapid-acting insulin analogues aspart and lispro, and/or the oral hypoglycaemic agents metformin and glibenclamide may be considered The fetus is at risk of macrosomia and hence birth trauma Insulin requirements cease after delivery of the placenta It is vital that a GTT is performed at 6 weeks after delivery and annually thereafter. The patient should be counselled with regard to her weight, diet and exercise. Without attention to this, more than 50% of women with gestational diabetes will develop true diabetes over the next 20 years. Contraception for patients with diabetes The following are important considerations: • • • • The combined pill (COP): associated with an increased risk of thrombosis, both venous and arterial. Nevertheless this would be suitable for the young woman with well-controlled diabetes and no evidence of vascular disease Progesterone-only pill: lower efficacy compared with the COP; greater likelihood of menstrual irregularities Intrauterine contraceptive device (IUCD): an effective method of contraception in diabetics. No evidence of reduced efficacy. A Mirena/IUS (intrauterine system) could also be considered Sterilisation: this is suitable for diabetic women who have completed their family, or wish to avoid pregnancy because of associated microvascular complications (severe retinopathy or nephropathy). 12.3.2 Cardiac disease and pregnancy The overall incidence of heart disease in pregnancy is increasing, with a prevalence of 8.8% of pregnancies, due to the development of corrective/palliative surgery over the last 30 years. There is also an increase in ischaemic heart disease. Cardiac disease remains the major cause of direct maternal mortality (Confidential Enquiry into Maternal and Child Health or CEMACH 2006–08). The haemodynamic changes that occur in pregnancy can be dangerous for women with cardiac disease. However, although the prognosis for pregnancy is generally good, in women with cardiac disease the exact level of risk posed by the pregnancy depends upon the underlying pathology: In general, regurgitant valvular lesions and mild/ moderate left-to-right shunts are well tolerated due to the decrease in total peripheral vascular resistance which occurs in pregnancy Conversely, stenotic valvular lesions, pulmonary hypertension and right-to-left shunts are poorly • tolerated. • It is therefore helpful to categorise heart disease in terms of mortality risk, because this will optimise accurate counselling, evaluation and management (Table 12.3). Table 12.3 Categorisation of heart disease in terms of mortality risk Risk Condition High (mortality rate 25–50%) Eisenmenger’s complex Cyanotic heart disease (tetralogy of Fallot, Ebstein’s anomaly, transposition of the great vessels) Pulmonary hypertension Acute myocardial infarction Hypertrophic obstructive cardiomyopathy Heart failure (including peripartum cardiomyopathy) Moderate to high (mortality rate 5–15%) Valvular stenosis Coarctation of the aorta History of myocardial infarction Marfan’s syndrome Mechanical prosthetic valve Low (mortality rate 1%) Acyanotic heart disease Mild-to-moderate valvular regurgitation Mitral valve prolapse Small ventricular septal defect Small atrial septal defect Symptoms and signs in normal pregnancy Symptoms of pregnancy may mimic cardiac disease, and dyspnoea, peripheral oedema and palpitations are all common complaints in normal pregnancy. A benign ejection systolic murmur occurs in 96% of pregnant women. ECG and echocardiographic changes in normal pregnancy • • ECG changes • Sinus tachycardia • Leftward or rightward shift of the QRS axis • Premature atrial or ventricular beats Echocardiographic changes • An increase in heart size and left ventricular mass • A small pericardial effusion • Mild valvular regurgitation Management of the pregnant woman with cardiac disease Preconception Management should take place in a multidisciplinary setting, preferably in a tertiary centre, and this should involve the obstetrician, cardiologist, anaesthetist and, if necessary, the cardiothoracic surgeon. Preconception evaluation will allow for appropriate counselling about maternal and fetal risks, optimisation of drug therapy and/or pre-pregnancy surgery if indicated. • Most cardiac drugs are safe, but ACE inhibitors should be avoided because they are associated with fetal and neonatal renal failure and death Anticoagulation: due to the hypercoagulable state of pregnancy, there is an increased risk of valve thrombosis and embolism in women with prosthetic valves. Warfarin is teratogenic, particularly in the first trimester, and is also associated with fetal haemorrhage throughout • pregnancy. Unfractionated heparin (UFH) does not cross the placenta, but is associated with maternal bone demineralisation and thrombocytopenia. In addition, heparin has also been associated with a higher risk of thromboembolic complications. Low-molecular-weight heparin (LMWH: twice daily regimen with close monitoring of anti-factor Xa levels) is the anticoagulant of choice for most women. The risks are less than those for UFH. Anticoagulation in these patients should be determined on an individual risk basis. Antenatal management Consideration should be given to the genetic implications of maternal cardiac disease. Congenital heart disease has a multifactorial inheritance. There is a small increase in the risk of congenital heart disease occurring in the fetus (3–5% dependent on the precise condition) but this risk increases sharply if more than one member of the family is affected. Consequently, high-resolution ultrasonography with fetal echocardiography is advised in the second trimester. • • • • • Once pregnant, most women will have no haemodynamic problems. Cardiac decompensation is, however, an indication for termination of pregnancy Fetal growth should be assessed regularly, particularly in women with severe heart disease and cyanotic congenital heart conditions Indications for cardiac surgery are the same as for the non-pregnant woman If surgery is required, it should be performed with the patient in the left decubitus position with provision for caesarean section if the gestation is >24 weeks Standard cardiopulmonary bypass may compromise the placenta and fetus due to hypothermia, reduced arterial perfusion and alterations in coagulation and acid–base balance. To avoid these complications, cardiopulmonary support should be high flow, normothermic and initiated without hyperkalaemic arrest. Intrapartum management The aim is to minimise cardiac strain. In general, spontaneous vaginal delivery (with limited active second stage (30 min)) is preferred but selected patients with severe heart disease may benefit from elective caesarean section. In labour, care must be taken to avoid supine hypotension due to aortocaval compression by the gravid uterus. • • • • In most with adequate cardiac reserve, epidural anaesthesia is effective and well tolerated. It should, however, be used with extreme caution in women with restricted cardiac outputs such as in primary pulmonary hypertension or right-to-left shunts. Under these circumstances, general anaesthesia and abdominal delivery may be preferred Fluid balance requires special attention and high-risk cases may warrant pulmonary wedge pressure monitoring with a pulmonary catheter Under certain circumstances, ergometrine should be avoided during the third stage of labour. The tonic contraction of the uterus caused by this drug will force approximately 500 mL of blood into the circulation, resulting in a rise in left atrial pressure. This would be particularly detrimental in patients with significant mitral stenosis. Alternative option is a slow intravenous infusion of Syntocinon (12 mU/min at 5 IU in 500 mL, rate 7 mL/h for 4 h) Delivery is associated with a transient asymptomatic bacteraemia. Therefore, women with structural heart disease may benefit from antibiotic prophylaxis (see guidelines from NICE). This is mandatory in women with prosthetic valves. Contraception Avoid the combined oestrogen/progesterone (COP) pill because of thrombosis risk. Implanon – a small implant that is inserted under the skin in the upper arm – delivers a continuous dose of the hormone etonogestrel. Failure rate is approximately 1 in 1000 per year. Implanon is one of the safest and most effective forms of contraception available. 12.3.3 Renal disease and hypertension in pregnancy Pregnancy outcome in women with renal disease has improved markedly in recent years. The main risks of pregnancy in a patient with renal disease are of adverse pregnancy outcome and deterioration of renal function accompanying the pregnancy. The risks depend on the following: • Degree of renal impairment at conception Presence of hypertension at conception or in early pregnancy (<20 weeks). Maintain ≤140/ 90 • mmHg • Degree of proteinuria (if >500 μmol/day refer to nephrologist). Risk is best determined by accurate assessment of renal function. Mildly impaired renal function In the presence of mildly impaired renal function (serum creatinine 125 μmol/L or GFR 50–70 mL/ min), the live birth rate approaches 95%. There is a slightly increased risk of preterm delivery, preeclampsia and fetal growth restriction (FGR), but pregnancy does not seem to adversely influence renal function. Therefore, women in this category should not be discouraged from becoming pregnant. Moderately impaired renal function In the presence of moderately impaired renal function (serum creatinine 125–250 μmol/L or GFR 25– 50 mL/min), there is a significantly increased risk (up to 50%) of preterm delivery, pre-eclampsia and FGR. The success of the pregnancy depends upon adequate control of blood pressure. Uncontrolled hypertension is associated with significantly increased rates of fetal and neonatal loss • There is a 25–50% chance of decline in renal function, which may be permanent Nevertheless, in a multidisciplinary setting and with rigorous control of blood pressure, the live • birth rate approaches 84%. • Severely impaired renal function In the presence of severely impaired renal function (serum creatinine ≥250 μmol/L or GFR ≤25 mL/ min), fertility is reduced. Spontaneous conception may occasionally occur. Again, the key to successful outcome is largely dependent on adequate control of maternal blood pressure. However, the risks to both the fetus and the mother are such that termination of pregnancy may be offered. • In women who continue with the pregnancy, there is a 90% chance of antenatal complications • Uncontrolled hypertension is associated with a 10-fold increase in perinatal mortality • The live birth rate is 50–80% (depending on underlying diagnosis and management). End-stage renal disease Patients who are receiving dialysis have very low fertility and, even if conception is successful, there is a high rate of miscarriage. There have only been a handful of reported cases of successful pregnancies in women receiving dialysis. In patients with functioning renal transplants, the outcomes are again determined by the level of graft (ie renal) function, as described above. Ideally, pregnancy should be avoided until 12 • months post-transplantation, by which stage graft function has stabilised and immunosuppressants are at maintenance levels only Most of the commonly used immunosuppressant agents (eg ciclosporin A, tacrolimus, prednisolone and azathioprine) are considered to be safe for administration during pregnancy. • Mycophenolate mofetil (MMF) should be avoided (both during pregnancy and for 3 months preconception), as teratogenic effects, including microtia (one or both ears have hearing loss), cleft lip and palate, have been reported with its use. Again, optimal blood pressure control is the key to a successful pregnancy. Specific renal diseases and pregnancy Specific renal diseases and their effects and outcome in pregnancy are given in Table 12.4. Management of pregnancy in patients with pre-existing renal disease The patients with pre-existing renal disease should be managed in a multidisciplinary setting. Where possible, the patients should be referred for preconception evaluation and counselling before embarking on a pregnancy. At this stage, there needs to be a consideration of possible genetic causes of renal impairment (eg polycystic kidney disease or Alport syndrome) which may affect the fetus. Once pregnant, the patient with renal disease should undergo the following management: • Early referral for antenatal clinic booking with accurate dating ultrasound scan • False-positive serum screening for T21 when creatinine ≥115 μmmol/L favours NT scanning Baseline biochemistry and urinalysis (including urea, creatinine, electrolytes, urate, lactate • dehydrogenase and urine protein:creatinine ratio (PCR). These investigations should be repeated at least every 4 weeks • Preferred antihypertensive drugs include labetalol, methyldopa and long-acting nifedipine ACE inhibitors should be discontinued preconceptually or at the earliest opportunity (see earlier • – 12.3.2 Cardiac disease in pregnancy) • The patient should be assessed frequently (fortnightly until 28 weeks, then weekly until delivery) Regular fetal surveillance with growth scans, commencing at 24 weeks (particularly if on • antihypertensive medication) Indications for preterm delivery are deteriorating renal function, the development of • superimposed pre-eclampsia and/or severe FGR. Hence, appropriate specialised paediatric services will be required Venous thromboembolism (VTE) risk: assessment particularly for those with proteinuria. • Thromboprophylaxis should be given to all with nephrotic syndrome. Table 12.4 Specific renal diseases and pregnancy Condition Possible complications that need Key management points monitoring Primary glomerulonephritis Hypertension; proteinuria; recurrent infection Treat associated clinical features; outcome relates to control of clinical features and severity of renal impairment Autosomal dominant polycystic kidney disease Impaired renal function; hypertension Make parents aware that the child has a 50% risk of inheriting the condition Increased risk of urinary tract obstruction, even if previously surgically corrected Perform kidney ultrasound in early pregnancy; serial assessment of renal function, urine culture, and blood pressure; repeat ultrasound if abnormalities in monitored parameters Congenital urinary tract obstruction Prophylactic antibiotics may Recurrent urinary tract infections; be needed; drainage of Vesicoureteric reflux nephropathy ureteral obstruction; pre-existing obstruction may also be renal impairment; hypertension necessary Magnetic resonance urography can be used in diagnosis to avoid exposure to radiation Nephrolithiasis Renal colic; ureteric obstruction Diabetic nephropathy Declining renal function in Try to maintain good women with pre-existing diabetic glycaemic control before, nephropathy; hypertension and during, and after pregnancy proteinuria Nephritis caused by systemic lupus erythematosus Can present like pre-eclampsia so Drug treatment managed by investigate for distinguishing rheumatologist and clinical and immunological obstetrician features Adjust dialysis to mimic the physiological changes of Haemodialysis is more effective than peritoneal Dialysis pregnancy Renal transplant Pre-eclampsia; fetal growth restriction; deteriorating graft function dialysis at mimicking physiological change Delay pregnancy until graft function and immunosuppression are stabilised The table above has been reproduced from Williams D et al., BMJ, Jan 26 2008, 336(7637): 211–215), with kind permission of the BMJ. 12.3.4 Antiphospholipid syndrome and pregnancy The antiphospholipid syndrome is defined as a clinical disorder with recurrent arterial and venous thrombotic events and/or pregnancy wastage in the presence of the lupus anticoagulant (LA) and/or a moderate-to-high positive anticardiolipin (ACL) test. The lupus anticoagulant is an inhibitor of the coagulation pathway. Its presence is a good predictor of poor fetal outcome. Anticardiolipin antibodies are antibodies active against certain phospholipid components of cell walls. They may be IgG or IgM Both a primary form (patients without clinical or serological evidence of autoimmune disorders), • and a secondary form (usually in patients with SLE) of the antiphospholipid syndrome are recognised. • Diagnosis of antiphospholipid syndrome requires two positive tests (LA and/or high titres of ACL, ie ≥40 GPL (IgG phospholipid units) or MPL (IgM phospholipid units), or ≥99th centile), at least 12 weeks apart, plus at least one of the following clinical scenarios: • • • • Vascular thrombosis – arterial, venous or small vessel thrombosis Pregnancy morbidity Recurrent miscarriage (three or more consecutive losses) Fetal loss after 10 weeks’ gestation (no fetal heart demonstrated on scan) Early onset (≤34 weeks’ gestation) preeclampsia and/or FGR (secondary to placental • dysfunction) • Placental abruption • Fetal death in utero or stillbirth. The mechanism of pregnancy loss/adverse pregnancy outcome is not clearly elucidated. Current theories include damage to placental vascular endothelium, platelet deposition, imbalance in the thromboxane:prostacyclin (PGI2) ratio and inhibition of protein C and tissue plasminogen. Inflammatory cytokines may also be implicated. Treatment The treatment options include oral therapy with low-dose aspirin (75 mg daily) and/or subcutaneous low-molecular-weight heparin (LMWH). Even with treatment the pregnancies can be complicated by hypertension and fetal growth restriction (FGR), and hence they require careful monitoring. Clinical trials indicate a ‘take-home baby rate’ of 70% with combined therapy versus 40% with aspirin alone. With no treatment, success is in the region of only 10% • See also Chapter 9, Haematology. • 12.3.5 Thyroid disease and pregnancy Thyroid disease is relatively common in women of childbearing age. Physiological changes during normal pregnancy include: • • • • • Increased thyroxine-binding globulin (TBG) (twofold) Increase in triiodothyronine (T3) and thyroxine (T4) secondary to oestrogen Relative iodine deficiency, increased renal excretion Free T4/T3 falls in the third trimester Thyroid-stimulating hormone (TSH) falls in first/ second trimester, and increases in third trimester. Serum screening is less accurate in hypothyroidism. Raised fetal TSH concentrations may falsely elevate both fetal and maternal serum AFP. This results in false-positive screening for neural tube defects and false negatives for trisomy 21 screening. Beta human chorionic gonadotrophin (βhCG) has weak thyroid-stimulating activity. Hyperthyroidism Untreated hyperthyroidism is associated with subfertility and reduced libido. It can also cause miscarriage, FGR/SGA, prematurity and stillbirth. It occurs with an incidence of approximately 1 in 500 pregnancies and is most frequently due to autoimmune thyrotoxicosis (Graves’ disease). Effect of pregnancy on hyperthyroidism • Flares are seen in both the first trimester, labour and the puerperium Typically remits in the second and third trimester, which results in a reduction in medication for • many, and cessation of therapy in about 30% The change in disease activity reflects the maternal immune state and titres of thyroid hormone • receptor-stimulating antibodies Effect of hyperthyroidism on pregnancy If hyperthyroidism is well controlled before and throughout pregnancy, outcomes are good for mother and baby Poor control is associated with excess nausea/vomiting, tremors, anxiety, arrhythmias, • congestive cardiac failure, preeclampsia, preterm labour, FGR and stillbirth • Treatment The treatment of choice is propylthiouracil or carbimazole. The dose is titrated against biochemical results (free T4 at the upper limit of normal, TSH in the normal range) and the maternal condition: About 30% of women require dose reduction or discontinuation in the second/third trimester, with possible increase/recommencement in the puerperium • A blocking/replacement regimen should be avoided in pregnancy. • Fetal and neonatal risks in thyrotoxicosis In pregnancy the aim of therapy is to reduce the dose of any drugs to the minimum required to control maternal disease. However, both propylthiouracil (PTU) and carbimazole cross the placenta, PTU less so. High dosage may be associated with fetal goitre, which usually resolves postnatally. Of babies, 10–20% have transient biochemical hypothyroidism which is rarely symptomatic and resolves on days 4–5 The fetal and neonatal risk of Graves’ disease is proportional to the titre of maternal TSH receptor-stimulating antibodies. These should be measured in the first and third trimester in • women with active disease, or in those with a history of disease treated with surgery and/or radioactive iodine. • Fetal hyperthyroidism develops between 20 and 24 weeks’ gestation. Complications of fetal hyperthyroidism • • • • • • • • Fetal tachycardia (>160 beats/min) Increased fetal movements FGR Fetal goitre Craniosynostosis Hydrops Polyhydramnios Preterm labour Treatment is dependent on gestation and is either delivery or anti-thyroid agents, titrated against fetal heart rate, movements and growth rate. Neonatal hyperthyroidism occurs in 1% of cases of maternal thyrotoxicosis. The clinical presentation may be delayed, but treatment with anti-thyroid drugs or β blockers is rarely needed for more than a few months. Clinical features of neonatal hyperthyroidism • • • • • • • Jitteriness Failure to gain weight Poor feeding Poor sleeping Bossing of frontal bones Liver dysfunction Jaundice Hypothyroidism Hypothyroidism is the most common pre-existing endocrine disorder in pregnancy. The incidence is 9 in 1000 pregnancies. The most common cause is Hashimoto’s thyroiditis. Treatment Thyroxine is the mainstay treatment, because it is safe in pregnancy and breastfeeding. Thyroid function tests should be measured at 8–12 weeks if stable, and every 4–6 weeks if the dosage is being adjusted Thyroxine should be altered according to the TSH levels. Maintain TSH <2.5 mU/L preconceptually and in the first trimester, <3.0 mU/L after this time. TSH may remain raised after the correct dosage has been achieved (especially in the third trimester). The dose should be • increased by 25–50% at the time of a missed period/positive pregnancy test to cope with the changing demands of pregnancy, which increase at 4–6 weeks until 16/20 weeks, when it plateaus. Suboptimal maternal treatment (ie TSH >2.5 mU/L preconceptually/first trimester) may be associated with miscarriage and/or adverse neurodevelopment in the child If the patient is stable pre-pregnancy (TSH <2.5 mU/L), she is likely to remain stable without • requiring any dose adjustment (beyond the initial increase) during the pregnancy • Neonatal hypothyroidism is rare and transient, and caused by TSH receptor-blocking antibodies. • Post-partum thyroiditis This has an autoimmune aetiology and hence it is associated with other autoimmune diseases. It has a prevalence between 5% and 8%. Thyroid anti-peroxidase antibodies are seen in 90% of women with the condition. The histology of the thyroid gland is typical of autoimmune thyroiditis with focal/diffuse thyroiditis, lymphocytic infiltration, follicular destruction and hyperplasia-destructive thyroiditis. There are three phases of post-partum thyroiditis: Thyrotoxicosis: 1–3 months post-partum. This is associated with low uptake of radioactive 1. iodine (unlike Graves’ disease). Treatment is rarely required, but if needed involves only β blockers Hypothyroidism: 3–8 months post-partum. This may be associated with symptoms that include 2. lethargy, poor memory and cold intolerance, and treatment with T4 may be indicated. Treat if symptomatic of TSH >10 mU/L 3. Normal thyroid function: by 1 year post-partum. The mother may experience one, two or all of these phases. The recurrence risk in another pregnancy is about 70%. Patients will need long-term surveillance as the risk of permanent hypothyroidism is about 3–5% per year (30% after 3 years). 12.3.6 Epilepsy and pregnancy Epilepsy occurs in 1 in 200 women of childbearing age, and is the most common neurological disorder in pregnancy. In general, the longer a woman has been free of fits before pregnancy the less likely it is that her epilepsy will deteriorate during pregnancy. Of women with active epilepsy, 1–2% will have a tonic–clonic seizure during labour, and a further 1–2% in the next 24 hours. Drug monitoring is not routinely recommended because there is no evidence that fit frequency relates directly to drug serum levels. Indications for monitoring are: detection of non-adherence, suspected toxicity, adjustment of phenytoin dose, management of pharmacokinetic interactions (eg changes in bioavailability), specific clinical conditions (eg status epilepticus), organ failure. Factors influencing fit frequency in pregnancy • • • • • • Disease pattern pre-pregnancy Sleep deprivation, especially in the third trimester Vomiting in pregnancy Altered protein binding, and increased volume of distribution of anticonvulsants Altered drug compliance Altered metabolism and excretion of anticonvulsant drugs Effect of maternal epilepsy upon the fetus The fetus is very tolerant of isolated, short-lived fits. Repeated fits can result in fetal hypoxia and lactic acidosis, which may be associated with fetal bradycardia and adverse effects. In rare instances, fetal intraventricular haemorrhages and death have been attributed to maternal convulsions. The effect may be remote and detected only in developmental delay years later. Status epilepticus doubles the risk of maternal death and is associated with a 50% miscarriage rate. Birth defects: epilepsy is associated with an increased incidence of certain congenital • malformations (3.5–4.5%); the risk is multifactorial and increases with sodium valproate (>800 mg/day) and the number of anticonvulsants used Risk of epilepsy in the newborn: depends on the type of epilepsy and the family history. For • idiopathic epilepsy, it is about 10% if one first-degree relative is affected and 25% if two or more first-degree relatives are affected Neonatal coagulopathy: associated with maternal use of phenytoin, phenobarbital and • primidone. Maternal coagulation studies are usually normal. Negated by giving infant 1 mg intramuscular vitamin K The incidence of stillbirth and perinatal deaths is higher in those exposed to antiepileptics in • pregnancy. Recognised increase risk of sudden infant death in women who discontinue antiepileptic drugs. Management of the epileptic in pregnancy • • • • • • Pre-pregnancy counselling should be given to the patient about the risks of pregnancy. Where possible, anticonvulsant monotherapy should be used. Consideration may be given to discontinuing anticonvulsants in women without fits Most women will have a healthy pregnancy but there may be an increased risk of complications High-dose folic acid (5 mg daily) should be advised preconceptionally and for the first 3 months of pregnancy (particularly for those women on hepatic enzyme-inducing antiepileptics such as phenytoin) A detailed fetal anomaly scan should be performed between 18 and 20 weeks If fits occur during pregnancy, the anticonvulsant levels should be monitored If the patient is receiving phenytoin, then vitamin K should be administered to the mother from 36 weeks’ gestation in order to counteract possible neonatal coagulopathy. 12.4 MEDICAL COMPLICATIONS OF PREGNANCY 12.4.1 Hypertensive disorders of pregnancy Definitions Hypertension in pregnancy is defined as follows: • Diastolic BP >110 mmHg on any one occasion or • Diastolic BP >90 mmHg on two or more consecutive occasions >4 h apart. Blood pressure should be measured in the sitting position with a sphygmomanometer cuff size appropriate for the size of the patient’s arm. Phases I and V of Korotkoff’s sounds identify the systolic and diastolic limits, respectively, correlating more accurately with outcome than phase IV. Mild hypertension: diastolic blood pressure 90–99 mmHg, systolic blood pressure 140–149 mmHg Moderate hypertension: diastolic blood pressure 100–109 mmHg, systolic blood pressure • 150–159 mmHg Severe hypertension: diastolic blood pressure ≥110 mmHg, systolic blood pressure ≥160 • • mmHg Proteinuria in pregnancy is defined as: • Total protein excretion >300 mg/24 h (with evaluation of the completeness of the sample) or • PCR spot test ≥30 mg/mmol. If an automated reagent device is ≥1+ a PCR should be undertaken in secondary care. A systematic review published in the BMJ in 2008 (Côté et al., 2008) concluded that the spot urinary protein:creatinine ratio is a reasonable ‘rule-out’ test for significant proteinuria of ≥0.3 g/day in pregnancy. Hypertension is associated with between 6% and 8% of pregnancies and can have serious repercussions for both fetal and maternal wellbeing. Hypertension can predate the pregnancy • (essential or chronic hypertension) or arise in pregnancy (pregnancy-induced hypertension or PIH) Most women with PIH have non-proteinuric PIH, a condition associated with minimal maternal • or perinatal mortality/morbidity • Approximately 2% of pregnancies are complicated by proteinuric PIH (pre-eclampsia). Pre-eclampsia is a serious pregnancy complication that causes significant maternal and perinatal morbidity. It is therefore imperative that every effort be made to accurately classify the nature of hypertension occurring in pregnancy because the aetiology and management of the three conditions, chronic hypertension, non-proteinuric PIH and preeclampsia, are very different (Table 12.5). Pre-eclampsia Although the primary events leading to preeclampsia are still unclear, it is now thought that the pathophysiology involves a cascade of events which leads to the clinical syndrome. Table 12.5 The International Society for the Study of Hypertension in Pregnancy classification (modified and abbreviated) 1. 2. Gestational hypertension and/or proteinuria developing during pregnancy (>20 weeks), labour or the puerperium in a previously normotensive non-proteinuric woman Gestational hypertension (without proteinuria) Gestational proteinuria (without hypertension) Gestational proteinuric hypertension (preeclampsia) Chronic hypertension (before the 20th week of pregnancy) and chronic renal disease (proteinuria before the 20th week of pregnancy) Chronic hypertension (without proteinuria) Chronic renal disease (proteinuria with or without hypertension) Chronic hypertension with superimposed preeclampsia (new-onset proteinuria) 3. Unclassified hypertension and/or proteinuria 4. Eclampsia Pathophysiology of pre-eclampsia • • • • • Genetic predisposition Release of circulating factor(s) Endothelial cell alteration Faulty interplay between invading trophoblast and decidua Decreased blood supply to the fetoplacental unit Pre-eclampsia is associated with hypertension, proteinuria and FGR. The maternal mortality rate is about 2% in the UK and, worldwide, 100 000 women die of preeclampsia each year. Perinatal mortality is also increased, and this is associated with FGR and iatrogenic preterm delivery. In the most recent CEMACH report (2006–08) hypertensive disorders of pregnancy are the fifth leading cause of direct maternal death. Screening for pre-eclampsia It is important to take a full history, because several factors can be associated with an increased risk of pre-eclampsia. Risk factors associated with pre-eclampsia • • Increased risk • Family history, 4–8 times higher in first-degree relatives • Primigravidas 15 times higher than multiparous • Longer pregnancy interval • Change in partner • Teenage pregnancy • Donor insemination • Medical disorders such as chronic hypertension, renal disease Decreased risk • Previous termination of pregnancy • Previous miscarriage • Non-barrier contraception • Increased duration of sexual cohabitation Biophysical tests All currently available tests are of limited clinical value. The uterine artery may appear ‘notched’ (Figure 12.1). Doppler waveforms may be of significance but they are only of sufficient sensitivity and specificity when used in a preselected high-risk population. Prophylaxis of pre-eclampsia Several agents have been investigated: • • • • • • • • • • • • • • Aspirin and a cyclo-oxygenase inhibitor. A Cochrane review of 42 randomised trials demonstrated a 15% relative reduction in the risk of pre-eclampsia with the use of aspirin or other antiplatelet agents NICE recommend starting aspirin before 12 weeks’ gestation in those who are at high/ moderate risk of developing pre-eclampsia Hypertensive disease during a previous pregnancy Chronic kidney disease Autoimmune disease such as systemic lupus erythematosus or antiphospholipid syndrome Type 1 or 2 diabetes Chronic hypertension First pregnancy Age ≥40 years Pregnancy interval of >10 years BMI of ≥35 kg/m2 or more at first visit Family history of pre-eclampsia Multiple pregnancy No evidence for calcium, fish oils containing omega-3 fatty acid or the antioxidant vitamins C and E. More recently the PELICAN study has been reported. Pre-eclampsia is a complex disease related to free radical damage and widespread oxidative stress and consequent damage of all blood vessels. Improved understanding of the underlying disease process has meant that a number of tests have been identified that might discriminate between those with preeclampsia and those without. In particular, this study evaluated placental growth factor (PlGF) as a marker of subsequent disease and harm, in women with suspected pre-eclampsia. Figure 12.1 (a) Normal uterine artery waveform; (b) high resistance uterine artery waveform Results have shown that the PlGF blood test is very good at predicting when women with preeclampsia will need to be delivered. Low PlGF concentration (<5th centile or ≤100 pg/ mL) has high sensitivity and negative predictive value in determining which women presenting with suspected disease at <35 weeks’ gestation are likely to need delivery for pre-eclampsia within 14 days. Time to delivery is markedly different for women with very low, low and normal PlGF values, facilitating stratified management strategies with appropriate surveillance. A trial comparing management of women with knowledge of PlGF to those for whom this knowledge is not available is now planned to determine whether pre-eclampsia can be diagnosed earlier. Maternal assessment in pre-eclampsia Several different organ systems can be affected in the pregnant woman: Platelets: consumed due to the endothelial activation. Although a platelet count of >50 × 109/L • will support normal haemostasis, a falling platelet count, particularly to <100 × 109/L, may • • • • • indicate a need to deliver Hypovolaemia: results in an increased haematocrit, with an apparent rise in the haemoglobin Clotting disorders: pre-eclampsia can cause disseminated intravascular coagulation, and clotting disorders must be assessed, particularly in the face of falling platelet numbers Renal tubular function: uric acid is a measure of ‘fine’ renal tubular function. It is used to assess the disease severity, although severe disease can still occur with a normal uric acid level. Spuriously high levels of uric acid are associated with acute fatty liver of pregnancy (see below) Renal impairment: raised urea and creatinine are associated with late renal involvement and hence are not useful as an early indicator of disease severity. However, serial measurements will identify renal disease progression. Proteinuria is a hallmark of pre-eclampsia; protein excretion may increase progressively as the pre-eclamptic process evolves Liver involvement: pre-eclampsia can cause subcapsular haematoma, liver rupture and hepatic infarction. Aspartate aminotransferase (AST) and other transaminases indicate hepatocellular damage. Elevated levels may again indicate a need to deliver. It should be remembered that the normal range for transaminases is approximately 20% lower than the non-pregnant range. The circulating albumin may fall, especially if urinary protein excretion is high (eg 3 g/24 h); hypoalbuminaemia increases the risk of pulmonary oedema. Note that a raised AST can be associated with either haemolysis or liver involvement; lactate dehydrogenase (LDH) levels are also elevated in the presence of haemolysis (see HELLP syndrome, on page 350). Fetal assessment in pre-eclampsia Fetal wellbeing must be carefully assessed in all cases of pre-eclampsia. This involves: Clinical assessment: the symphyseal–fundal height should be carefully measured and an enquiry as to fetal movements undertaken Investigations: regular ultrasound assessment of fetal growth and amniotic fluid volume should • be performed. Umbilical artery Doppler waveforms may be of use. • Suspected fetal compromise is a frequent indication for delivery in pre-eclampsia. Management of pre-eclampsia Pre-eclamptic hypertension can cause direct arterial injury which can, in turn, predispose to possibly fatal cerebral haemorrhage. In order to prevent this injury, severe hypertension should be avoided. Blood pressure >170/110 mmHg (mean arterial pressure [MAP] ≥140 mmHg) requires urgent therapy. The rationale for treating moderate hypertension (BP >140/90 mmHg, but <170/110 mmHg) is less clear. In the most recent CEMACH report, attention was particularly drawn to the importance of treating systolic hypertension (ie SBP >160 mmHg), in line with the recent guidelines from NICE, irrespective of the MAP, because of the risk of maternal cerebral haemorrhage. Consideration should also be given to initiating treatment at lower pressures if the overall clinical picture suggests rapid deterioration and/or where the development of severe hypertension can be anticipated. The target systolic blood pressure after treatment is 150 mmHg. Choice of antihypertensive agents: methyldopa, labetalol and nifedipine are the mainstay in therapy. In practice, the choice of agent probably matters less than the clinician’s familiarity with it. Timing of delivery: in women with established preeclampsia, delivery should be considered once fetal lung maturity has been achieved. However, in asymptomatic women with pre-eclampsia presenting between 26 and 34 weeks, management can often be expectant in an attempt to achieve improved perinatal survival, without substantial risk to the mother. This does, however, require close inpatient supervision in a unit with adequate numbers of appropriately skilled staff. Trials have confirmed the advantages of this cautiously expectant approach. Delivery before 37 weeks’ gestation is NOT required if BP <160/110 mmHg (NICE). As stated previously, fetal compromise will indicate the need for delivery. Indications for delivery in pre-eclampsia • • • • • • Refractory severe hypertension Deteriorating liver or renal function Progressive fall in platelets Neurological complications Abnormal CTG, abnormal Doppler Deteriorating fetal condition Postnatally: monitor BP daily for 2 days and then at least once between days 3 and 5. Consider reducing antihypertensive treatment if BP falls to <140/ 90 mmHg, and reduce antihypertensive treatment if BP falls to <130/80 mmHg. Maintain therapy for at least 2 weeks and review in secondary care at 6–8 weeks. HELLP syndrome HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome is a severe form of preeclampsia, associated with: • Haemolysis • Elevated liver enzymes (ALT/LDH) • Low platelets. It complicates about 10–15% of cases of preeclampsia. Mortality rates vary from 0% to 25%, and mortality is associated with cerebral haemorrhage and disseminated intravascular coagulation (DIC), correlating with the extent of thrombocytopenia. HELLP syndrome and acute fatty liver of pregnancy are two conditions that are very similar and there is a recognised degree of overlap in both aetiology and pathophysiology, such that a definitive diagnosis can be difficult to make. Acute fatty liver of pregnancy Acute fatty liver of pregnancy typically occurs in obese women or in the third trimester of pregnancy. It is associated with pre-eclampsia (30–100% of cases) and twin pregnancy, and is more common in women with male fetuses. Symptoms develop acutely and include abdominal pain, nausea/vomiting, headache and jaundice. Other clinical features that may occur include pruritus, fever, enterocolitis, ascites or pancreatitis. Investigations in acute fatter liver of pregnancy • • • Laboratory findings: • Neutrophil leukocytosis • Increased fibrin degradation products • Low platelets • Microangiopathic haemolytic anaemia • Increased bilirubin • Raised AST (3–10 times above normal) • Hypoglycaemia • Increased uric acid Liver pathology: • The liver is small and yellow Histology reveals microvesicular steatosis with intrahepatic cholestasis and canalicular • plugs of bile; distribution is panlobular with sparing of periportal areas • Extramedullary haematopoiesis Imaging: Increased reflectivity of liver on ultrasound scanning and lower attenuation on MRI are • both indicative of ‘fat’ within the liver Infarction appears as multiple non-enhancing lesions of low attenuation, with mottled • appearance Management of acute fatty liver of pregnancy Early diagnosis is important, followed by transfer of the patient to tertiary care. The patient may need to be transferred to intensive care for correction of hypertension, hypoglycaemia and bleeding diathesis. The baby needs to be delivered as a matter of urgency. The neonate is at risk of fatty infiltration of the liver and this is associated with impaired liver function, hypoglycaemia, thrombocytopenia and neutropenia. Eclampsia Eclampsia is defined as convulsions occurring in a woman with pre-eclampsia in the absence of any other neurological cause. The maternal mortality associated with eclampsia in the UK is approximately 1 in 50. It complicates 1 in 2000 pregnancies in the UK. In about 40% of cases it is totally or partially unheralded by prodromal signs or symptoms. In 10% of cases the only warning sign is proteinuria, and in another 20% there is hypertension only. Most cases occur during labour or after delivery. Such cases are usually at term and in hospital. Preterm eclampsia is more likely to be antepartum. Management of eclampsia The aim of management is to protect the maternal airway and control the convulsions and extreme hypertension, as well as to expedite delivery. Choice of anticonvulsant: most fits stop quickly and spontaneously. In the Collaborative Eclampsia Trial (1995) magnesium sulphate was shown to be the anticonvulsant of first choice. • A bolus of 4 mg is given intravenously over 10 minutes. About 10% of all fits will not be controlled by magnesium sulphate. A brain scan should be performed if presentation is atypical, if any focal signs develop, or in the case of repeated or prolonged seizures. Magnesium sulphate treatment in eclampsia • • • • Toxic side effects: muscular weakness; respiratory paralysis; heart failure and death Monitor: check deep tendon reflexes Therapeutic levels: 2–3.5 mmol/L Antidote: calcium gluconate 1 g over 10 min, intravenously Prophylactic use of magnesium sulphate may be considered in women with the following: • • Severe hypertension and proteinuria or Mild or moderate hypertension and proteinuria with one or more of the following: • symptoms of severe headache • problems with vision, such as blurring or flashing before the eyes • severe pain just below the ribs or vomiting • papilloedema • signs of clonus (≥3 beats) • liver tenderness • HELLP syndrome • platelet count falling to <100 × 109/L • abnormal liver enzymes (ALT or AST rising to above 70 IU/L). Long-term risks • Women with pre-eclampsia are at risk of complications later in life • These women are also at risk in a subsequent pregnancy Risk of gestational hypertension in a future pregnancy ranges from about one in eight (13%) • pregnancies to about one in two (53%) pregnancies Risk of pre-eclampsia in a future pregnancy is up to about one in six (16%) pregnancies (one in • four and one in two, respectively, if severe disease, HELLP and/or eclampsia necessitating delivery <34 or <28 weeks’ gestation) Chronic hypertension Chronic hypertension (CHT) is detected by either an antecedent medical history or a raised blood pressure in the first half of pregnancy. The physiological decline in the blood pressure in early pregnancy is exaggerated in women with CHT so that they may be normotensive. Conversely, in later pregnancy the normal rise in blood pressure is exaggerated in patients with CHT. Hence a woman with CHT may be normotensive initially, with hypertension only appearing in the third trimester. • • • • • • CHT in pregnancy is a major predisposing factor for pre-eclampsia. This risk is about five times greater than in normotensive women Women with CHT who do not develop preeclampsia can usually expect a normal, uncomplicated perinatal outcome, although there is some evidence for a modest increase in the incidence of FGR in these women. Perinatal morbidity and mortality is related to treatment and so cautious discontinuation of pharmacological agents may be appropriate (see later) Pregnant women with uncomplicated chronic hypertension should be treated with the aim of keeping BP <150/100 mmHg Pregnant women with target-organ damage secondary to chronic hypertension (eg kidney disease) should be treated with the aim of keeping BP <140/90 mmHg High BP in pregnancy is associated with risks for mother and baby. However, there is no agreement about whether antihypertensives should be given for non-severe hypertension in pregnancy. Some clinicians treat mild-to-moderate hypertension whereas others give medication only once persistent severe hypertension has developed. The CHIPS (Control of Hypertension in Pregnancy Study) randomised women with mild-to-moderate hypertension to ‘tight’ blood pressure control or ‘less tight’ control (ongoing – anticipated completion March 2014) Antihypertensive treatment: ACE inhibitors and ARBs should be avoided, because these classes of drugs are associated with fetal and neonatal renal failure and death. Women with mildto-moderate hypertension should discontinue treatment before conception because of the risk of FGR. There is no evidence that treating CHT reduces the risk of superimposed pre-eclampsia, nor is there any evidence to support a particular fetal benefit. Long-term use of antihypertensive drugs has been associated with FGR; it is uncertain whether this is a specific drug effect (eg β blockers) or a consequence of a reduction in placental perfusion after a lowering of arterial pressure. 12.4.2 Thrombotic complications in pregnancy Thromboembolic disease Pulmonary embolism is one of the leading causes of maternal mortality in the UK. Although that risk is reducing (sixth in the 2006–08 report), pregnancy is a procoagulant state and increases the risk of thromboembolism by about sixfold. The absolute incidence varies widely between 0.1% and 1.2% of all pregnancies. Deep vein thrombosis (DVT) is about twice as common as pulmonary embolism. The risk of thrombosis is as common in the first trimester as in the third. Aetiology Pregnancy is a hypercoagulable state due to an increase in factors VII, VIII and X, as well as fibrinogen and prothrombin. This is exacerbated by venous stasis because the gravid uterus obstructs the inferior vena cava, causing a decrease in venous tone in the lower limbs, which is greater on the left than the right (hence 80% of DVTs occur on the left). Immobility during labour and in the postpartum period, particularly after surgical delivery, further exacerbates the situation. Other factors are listed in Table 12.6. Obesity remains the most important risk factor for thromboembolism (CEMACH). Risk assessment in early pregnancy continues to be a key factor in reducing mortality. This should be undertaken repeatedly, assessing for additional risk factors to include admission to hospital, and again intrapartum and post-partum Women are at risk of thromboembolism from the very beginning of pregnancy until the end of the puerperium, and all health professionals must be aware of this. Chest symptoms appearing for the first time in pregnancy or the puerperium in at-risk women need careful assessment, and there should be a low threshold for investigation Thrombophilia Thrombophilic tendencies may be more significant in women of reproductive age because pregnancy may uncover a hitherto unrecognised condition (Robertson et al., 2006). The following are main conditions to consider: Table 12.6 Other factors increasing the risk of thromboembolism in pregnancy/puerperium Increased with age (>35 years) Increased with rising parity (>3) Multiple pregnancy OHSS (ovarian hyperstimulation syndrome) Increased body mass index (three times increased risk if BMI >29) Smoking, because it causes inhibition of fibrinolysis Sickle cell disease Pre-eclampsia Proteinuria Dehydration – hyperemesis Sepsis Varicose veins – symptomatic, above knee, associated phlebitis Blood group other than O Thrombophilic conditions (see below) PPH >1L Lower segment caesarean section Protracted labour (>24 h) Trial of rotational surgical delivery • Antithrombin deficiency • Antiphospholipid deficiency/Lupus anticoagulant syndrome • Protein C deficiency • Protein S deficiency • Prothrombin gene variant (see below) (Coulam, 2006) • Factor V Leiden (see below). Homocystinuria Hereditary thrombophilic states may be associated with an adverse pregnancy outcome including: early pregnancy loss (odds ratio [OR] 1.40–6.25); late pregnancy loss (OR 1.3–20.09); preeclampsia (OR 1.37–3.49); placental abruption (OR 1.42–7.71); and FGR (OR 1.24–2.92). Lowdose aspirin plus LMWH was the most effective in preventing pregnancy loss in acquired thrombophilias (OR 1.62). With regard to hereditary thrombophilias, despite the increase in relative risk, the absolute risk of venous thromboembolism (VTE) and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. The association with recurrent miscarriage is probably limited to those women with acquired rather than hereditary thrombophilias or those with compound thrombophilias. Similarly there is now evidence to suggest that a single gene variant (to include heterozygosity for factor V Leiden and/or PGV) alone is in itself a relatively weak risk factor for VTE (and/or adverse pregnancy outcome) and is therefore not an indication for antenatal LMWH, with the exception of antithrombin III deficiency. Rather, it should be considered in the light of other risk factors for VTE. Antithrombin deficiency Two types of antithrombin deficiency exist: • Type I – a deficiency of a normal molecule • Type II – associated with an abnormal molecule. The risk of thromboembolism is as high as 40–70% and necessitates lifelong warfarin. The risk is greater in type I than type II antithrombin deficiency. In pregnancy, patients with types I and II antithrombin deficiency (plus additional risk factors; see Table 12.6 for other factors increasing the risk of thromboembolism) should receive therapeutic levels of LMWH. Antithrombin concentrate may be required to cover labour and if thrombosis occurs earlier in pregnancy. Cord blood should be taken to assess neonatal status at birth; tests should be repeated at 6 months. Antiphospholipid syndrome Antiphospholipid deficiency/lupus anticoagulant have been considered earlier (see section 12.3.4). Protein C deficiency Protein C deficiency may be inherited in autosomal dominant and recessive forms. Patients will often have a history of thrombosis. These patients require thromboprophylaxis with antiembolic stockings and LMWH throughout the antenatal period and for 6 weeks post-partum. In those women without a personal history of thrombosis, additional risk factors need to be considered (eg BMI >30, age >35 years, parity >3, immobility >4 days) in deciding whether to use LMWH – all women require antiembolic stockings. Warfarin is avoided because it is associated with skin necrosis (purpura fulminans in those women with the homozygous form) and both teratogenicity (greatest risk between 6 and 12 weeks’ gestation) and fetal intracerebral bleeding (throughout the second and third trimesters). Prenatal diagnosis is achieved by cordocentesis in the second trimester. Protein S deficiency Protein S is a cofactor for protein C and levels normally fall in pregnancy, making diagnosis difficult. Deficiency of protein S is associated with a 0–6% risk of thrombosis antenatally and 7–22% postnatally. The usual approach is to treat with prophylactic doses of LMWH in the post-partum period only, unless additional risk factors exist. Factor V Leiden Factor V Leiden is caused by a single point mutation. It is resistant to activated protein C, causing thrombosis. Two forms of factor V Leiden exist: 1. Heterozygous: more common; risk of thrombosis 0.25% (Table 12.7) 2. Homozygous: rare; risk of thrombosis 50–80 times greater than in non-carriers. The risk of thrombosis is low in heterozygotes, particularly in the absence of a personal history of thrombosis and/or additional risk factors. Prophylaxis, in the form of compression stockings, may be offered. LMWH is usually reserved for those women who are homozygous for the gene or have additional risk factors. Recent evidence refutes its association with recurrent miscarriage and/or poor pregnancy outcome (see earlier). Prothrombin gene variant Similar to factor V Leiden above. There are heterozygous and homozygous forms. LMWH is considered if additional risk factors and/or postnatally. Homocystinuria Homocystinuria is an inborn error of metabolism that is associated with increased risk of both arterial and venous thrombosis. The absolute risk of VTE in pregnancy is low. It should be considered alongside other risk factors. Women should be offered high-dose folic acid. LWMH is not indicated (RCOG). Table 12.8 gives the prevalence and risk of VTE during pregnancy in relation to inherited thrombophilias. Diagnosis of thromboembolic disorders in pregnancy Table 12.9 outlines the diagnosis of thromboembolic disorders in pregnancy. Treatment of thromboembolic disorders Warfarin is generally avoided in pregnancy. In the first trimester it is associated with an increased risk of miscarriage and teratogenic side-effects which include chondrodysplasia punctata, asplenia and diaphragmatic hernia. In the second and third trimesters it is associated with retroplacental and intracerebral fetal haemorrhage, as well as fetal microcephaly, optic atrophy and developmental delay. It is safe for breastfeeding. Table 12.7 Thrombophilic or hereditary hypercoagulable disorders in the general population andinpeoplewith venous thrombosis Condition Prevalence in people Prevalence in general with venous population (%) thrombosis (%) Increased risk for thrombosis Factor V Leiden Prothrombin 20210A Protein C Protein S Antithrombin III 5–15 1–6 0.2 Unknown 0.02 3.8 3.0 25–50 10–15 10 20 2 3 1–2 1 Table 12.8 Prevalence and risk of venous thromboembolism (VTE) associated with pregnancy in relation to inherited thombophilias Thrombophilia Factor V Leiden (heterozygous) Factor V Leiden (homozygous) Prothrombin gene mutation (heterozygous) Prothrombin gene mutation (homozygous) Compound heterozygote (factor V Leiden and prothrombin gene mutation) Antithrombin deficiency (<80% activity) Protein C deficiency (<75% activity) Protein S deficiency (<65% activity) Prevalence among women with VTE associated with pregnancy (%) Relative risk of VTE 8–44 9–17 3–17 – 5–10 10–80 2–5 – 4–9 9–107 12–60 AN; 11–33 PPa 3–10 AN; 7–19 PPa 0–6 AN; 7–22 PPa 10 to unknown Unknownb Unknownb AN, antenatal; PP, post-partum. a For women with protein C or protein S deficiency the risk of VTE is greater post-partum. Conversely, with antithrombin deficiency the risk of VTE is greatest during pregnancy. b Overall annual incidence of VTE in patients with protein S deficiency or protein C deficiency is 3.5% and 2.5%, respectively (Pabinger IPA et al. The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study. Thromb Haemost 1994;71:441–5.) LMWH is the mainstay of treatment (but also note use of aspirin in antiphospholipid syndrome). LMWH is preferred to unfractionated heparin because it is less frequently associated with bleeding, thrombocytopenia and osteopenia. Post-partum thromboprophylaxis • All women should be encouraged to mobilise both during labour and post-partum, and dehydration should be avoided • Women with two or more risk factors should be considered for LMWH for 7 days after delivery Women with three or more persisting risk factors should be given graduated compression • stockings in addition to LMWH 2 • All women with BMI >40 kg/m should be considered for thromboprophylaxis with LMWH for 7 days after vaginal delivery, 6 weeks after LSCS (lower segment caesarean section). Women receiving LMWH antenatally should usually continue prophylactic doses of LMWH until 6 weeks post-partum – which can be converted to warfarin soon after delivery Air travel in pregnancy (RCOG) A particular concern is the risk of DVT. This risk is likely to be increased (threefold) by air travel owing to immobility, and/or potentially cramped conditions, with an 18% higher risk of VTE for each 2-hour increase in flight duration. Nevertheless, the overall absolute incidence of a symptomatic VTE is low, with a rate of 1 in 4600 flights in the month after a 4-hour flight. The risk will vary according to the individual’s own risk factors for thrombosis. With regard to minimising the risk of DVT, the following would be the appropriate general advice: • Have an aisle seat to facilitate ease of movement Take regular walks around the cabin and/or carry out in-seat exercises approximately every 30 • min on a medium- or long-haul flight • Maintain a good fluid intake and minimise caffeine and alcohol intake to avoid dehydration Make a specific individualised risk assessment for thrombosis in pregnant women who are • flying. Table 12.9 Diagnosis of thromboembolic disorders in pregnancy Disorder Deep vein thrombosis Pulmonary Diagnostic tool Description Clinical and laboratory The clinical diagnosis of deep vein thrombosis (DVT) in pregnant women can be difficult However, 70% are iliofemoral and therefore clinically obvious, with a tender, swollen painful leg D-dimers are raised in normal pregnancy. They do, however, provide a useful negative Doppler ultrasonography Most widely used technique; effective in diagnosis of symptomatic, proximal DVT. If clot is present the vein is incompressible and does not dilate during the Valsalva manoeuvre; sensitivity/specificity about 97%. Insensitive for thrombosis within the calf, or above the inguinal ligament Chest radiograph Confers minimal risk to fetus. Often normal but may demonstrate an effusion, decreased vascularity embolism ECG Note that changes can occur within normal pregnancy. In pulmonary embolism (PE) the ECG may be normal, or it may demonstrate a sinus tachycardia, right heart strain or the classic features of a deep S wave in I, Q wave and inverted T wave in III Blood gas analysis May be normal but in the presence of a PE will typically demonstrate hypoxia with ↓ PaO2, and normal or ↓ PaCO2 V′/Q′ scan The isotopes used have short half-lives and so exposure of the fetus is minimal. The V′/Q′ scan can be safely performed in breastfeeding mothers. False negatives are rare and hence a normal scan excludes PE. The typical features are perfusion defect with normal ventilation. Moderate probability scans should be discussed with a respiratory physician. Undertake leg Doppler FIRST CTPA (CT pulmonary angiogram) should be considered first line (after leg Doppler) in those patients with additional lung pathology, abnormal chest radiograph, or after a low probability scan when the clinical picture fails to improve or worsens despite thromboprophylaxis, and the underlying diagnosis has not been established For short-haul journeys: no specific measures are likely to be required. For medium- to long-haul flights (≥4 hours): all pregnant women are advised to wear properly fitted, graduated, elastic compression stockings. For women with additional risk factors for thrombosis such as morbid obesity, specific prophylaxis with LMWH should be considered for the day of travel and several days thereafter, if the woman is not already on LMWH. The appropriate duration of thromboprophylaxis is not yet established and is a matter for clinical judgement. FURTHER READING Chappell LC, Duckworth S, Seed PT, et al. PELICAN – Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation 2013;128:2121–31. Côté A-M, Brown MA, Lam E, et al. Diagnostic accuracy of urinary spot protein:creatinine ratio for proteinuria in hypertensive pregnant women: systematic review. BMJ 2008;336:1003. Coulam CB. Multiple thrombophilic gene mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol 2006;55:360–8. National Institute for Health and Care Excellence. Diabetes and Pregnancy. Guideline 68. London: NICE, 2008. National Institute for Health and Care Excellence. Hypertension in Pregnancy. Guideline 107. London: NICE, 2011. Robertson L, Wu O, Langhorne P, et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006;132:171–96. Royal College of Obstetricians and Gynaecologists. Thrombosis and Embolism in Pregnancy and the Puerperium – Reducing the risk. Guideline 37a. London: RCOG, 2009. Royal College of Obstetricians and Gynaecologists. Cardiac Disease in Pregnancy. RCOG Good Practice. London: RCOG, 2011. Chapter 13 Metabolic Diseases CONTENTS 13.1 Disorders of amino-acid metabolism 13.1.1 Alkaptonuria (ochronosis) 13.1.2 Cystinosis 13.1.3 Cystinuria 13.1.4 Homocystinuria 13.1.5 Primary hyperoxaluria (oxalosis) 13.1.6 Phenylketonuria 13.2 Disorders of purine metabolism 13.2.1 Gout 13.2.2 Lesch–Nyhan syndrome 13.3 Disorders of metals and metalloproteins 13.3.1 Wilson’s disease 13.3.2 Haemochromatosis 13.3.3 Secondary iron overload 13.3.4 The porphyrias 13.4 Disorders of lipid metabolism 13.4.1 Lipid metabolism 13.4.2 The hyperlipidaemias 13.4.3 Lipid-lowering drugs 13.4.4 Rare lipid disorders 13.5 Disorders of bone, mineral metabolism and inorganic ions 13.5.1 Calcium homeostasis 13.5.2 Hypercalcaemia 13.5.3 Hyperparathyroid bone disease 13.5.4 Hypocalcaemia 13.5.5 Hypercalciuria 13.5.6 Osteomalacia 13.5.7 Paget’s disease 13.5.8 Osteoporosis 13.5.9 Disorders of magnesium 13.5.10 Disorders of phosphate 13.6 Nutritional and vitamin disorders 13.6.1 The obesity and diabetes epidemic 13.6.2 Protein–energy malnutrition 13.6.3 Vitamin deficiencies 13.7 Metabolic acid–base disturbances (non-renal) 13.7.1 Metabolic acidosis 13.7.2 Metabolic alkalosis 13.8 Hypothermia 13.8.1 Treatment of hypothermia Metabolic Diseases 13.1 DISORDERS OF AMINO-ACID METABOLISM Most of the inherited metabolic diseases are Mendelian, single-gene defects, transmitted in an autosomal recessive manner. Disease expression requires the affected individual to be homozygous – inheriting a mutant gene from each of their parents, who are both heterozygous for the defect. Although heterozygotes may synthesise equal amounts of normal and defective enzymes they are usually asymptomatic. Even the major inborn errors of amino-acid metabolism are rare – phenylketonuria, one of the most common, has an incidence of 1/20 000 • Complete penetrance is common and the onset is frequently early in life The consequences of these enzyme deficiencies are varied and frequently multisystem but • expression tends to be uniform. • The more common of these conditions are listed in the box below and the major inborn errors of amino-acid metabolism are then discussed. Inborn errors of amino-acid metabolism • Albinism • • • • • • • • Alkaptonuria Cystinosis Cystinuria Homocystinuria Histidinaemia Maple syrup urine disease Oxalosis Phenylketonuria 13.1.1 Alkaptonuria (ochronosis) This is a rare autosomal recessive disease with an incidence of 1/100 000. Homogentisic acid accumulates as a result of a deficiency in the enzyme homogentisic acid oxidase. • • • • • • • The homogentisic acid polymerises to produce the black–brown product alkapton, which becomes deposited in cartilage and other tissues (ochronosis) Classic features include pigmentation (dark blue, grey or black) of the sclerae, ears, arthritis, intervertebral disc calcification and dark sweat-stained clothing Life expectancy is normal but there is significant morbidity from joint complications. Onset of back pain is around 30 years Rarer manifestations include renal stone disease as well as aortic valve and ocular involvement The urine darkens on standing because homogentisic acid conversion to alkapton is accelerated in alkaline conditions There is a high prevalence of alkaptonuria in Slovakia (1/19 000) due to novel mutations, which have resulted in geographical clustering The molecular basis of the disorder is known but there is no specific treatment. Vitamin C is sometimes recommended as a mild antioxidant. Arthritis may require joint replacement. 13.1.2 Cystinosis Cystinosis is an autosomal recessive lysosomal storage disease which occurs with an approximate frequency of 1/100 000 to 1/200 000 live births. In cystinosis, cystine accumulates in the reticuloendothelial system, kidneys and other tissues. There is a defect of cystine transport across the lysosomal membrane resulting in widespread intralysosomal accumulation of cystine. The causative gene (CTNS), which encodes for an integral membrane protein called cystinosin, has been identified on chromosome 17p13. Unlike cystinuria, stones do not occur in this condition. Clinical features of cystinosis • Fanconi syndrome (often with severe hypophosphataemia and consequent vitamin D-resistant rickets) • Lymphadenopathy • Severe growth retardation • Insulin deficiency • Corneal opacities and photophobia • Abnormalities of cardiac conduction • Hypothyroidism • Bone marrow failure • Central nervous system (CNS) involvement Onset is usually in the first year of life and chronic kidney disease (CKD) is progressive, often resulting in end-stage renal disease by the age of 10 years. Corneal or conjunctival crystals usually suggest the diagnosis, which can be confirmed by measuring the cystine content of neutrophils or cultured fibroblasts. Specific therapy with cysteamine bitartrate is effective at reducing cystine accumulation and delaying CKD. Cysteamine eye drops can be used to help with corneal disease. Supportive care, including dialysis and transplantation, is usually needed. Cystinosis does not recur in the transplant but extrarenal disease is progressive. Antenatal testing for cystinosis can be performed by measuring cystine levels in chorionic villi or cultured amniotic fluid cells. Ocular non-nephropathic cystinosis: this is a variant of the classic disease and is due to • different mutations of the cystinosis gene CTNS. It is an autosomal recessive lysosomal storage disorder characterised by photophobia due to corneal cystine crystals. 13.1.3 Cystinuria Cystinuria is an autosomal recessive disorder with a prevalence of about 1/7000. The transport of cystine and the other dibasic amino acids lysine, ornithine and arginine is abnormal in the proximal renal tubule and the jejunum. • No malnutrition occurs as sufficient dietary amino acids are absorbed as oligopeptides • Presentation is usually in the second or third decade of life with renal stones Cystine accumulates in the urine. It is highly insoluble at acid pH and this results in the formation • of radio-opaque calculi (cystine stones account for 1–2% of all urinary tract stones). A urinary cystine concentration >1 mmol/L (at pH 7.0) is supersaturated and leads to calculi formation. Diagnosis requires measurement of urinary cystine and/or chromatographic analysis of the stone. Pathognomonic hexagonal crystals can be found on urine microscopy. Management Management involves large fluid intake, alkalinisation of urine and D-penicillamine (which chelates cystine and increases its solubility). Tiopronin is an alternative and increasingly first-line cystine chelator that is better tolerated than D-penicillamine. Captopril is a thiol angiotensin-converting enzyme (ACE) inhibitor and consequently can bind to cystine and increases its solubility. 13.1.4 Homocystinuria This rare autosomal recessive abnormality results from reduced activity of cystathionine synthase. The resulting homocystine and methionine accumulation interferes with collagen cross-linking. Nearly a quarter of patients die as a result of vascular thrombosis before the age of 30. Clinical features of homocystinuria • • • • • • • Downward lens dislocation Venous and arterial thromboses Spontaneous retinal detachment Developmental and learning disability Osteoporosis Seizures and psychiatric syndromes Skeletal abnormalities (eg marfanoid stature, arachnodactyly, chest deformities) The main differential diagnosis is Marfan syndrome, because patients can have similar skeletal manifestations and ectopia lentis (although this is classically upward lens dislocation in Marfan syndrome). Osteoporosis, learning disability and vascular thrombosis do not occur in patients with Marfan syndrome. Investigations Tests show elevated plasma-free methionine and homocystine. Diagnosis is established by the cyanide/nitroprusside test that detects elevated urinary homocystine and reduced cystathionine synthase enzyme activity in tissue (liver or skin biopsy). Heterozygous carriers have elevated serum homocystine but no homocystinuria. Premature cardiovascular risk is also increased in heterozygotes. Management • • • • • Early detection (of younger siblings) Methionine restriction and cystine-supplemented diets Pyridoxine supplements (effective in 50%) Some variants are responsive to folate or vitamin B12 supplements Antenatal screening for enzyme deficiency is available. Other causes of elevated plasma homocystine Plasma homocystine levels can be elevated in elderly people, postmenopausal women and patients with advanced CKD and hypothyroidism. Drug treatments such as methotrexate can also increase levels. Elevated homocystine levels have been associated with an increased risk of cardiovascular disease (eg in dialysis populations) and deep vein thrombosis. 13.1.5 Primary hyperoxaluria (oxalosis) There are two inborn errors of metabolism that cause overproduction of oxalate. Both are autosomal recessive and can lead to hyperoxaluria with stones and tissue deposition of calcium oxalate. • Type I is due to a deficiency of hepatic peroxisomal alanine:glyoxylate aminotransferase • Type II is due to a deficiency of D-glyceric acid dehydrogenase. Clinical features of oxalosis • • • • • Oxalate renal stones Severe arterial disease (due to deposition of oxalate crystals in the vessel wall) Nephrocalcinosis Cardiac disease (conduction delay) Bone disease (and bone marrow invasion leading to pancytopenia and fractures) Diagnosis Oxalosis should be suspected if there is increased urinary oxalate excretion, but the latter can also occur with pyridoxine deficiency (as this is a necessary coenzyme in oxalate metabolism), ileal disease, ethyl glycol poisoning and excess oxalate ingestion. Confirmation of diagnosis requires: • Plasma oxalate • Liver biopsy to demonstrate enzyme deficiency in type I • Demonstration of enzyme deficiency in peripheral blood leukocytes in type II Genetic testing by mutation and linkage analysis is useful for identifying other affected family • members, as well as in prenatal diagnosis and carrier testing. Treatment of oxalosis This initially involves high fluid intake, urinary calcium crystallisation inhibitors (eg citrate) and the use of pyridoxine. Only 10–30% of patients respond to pyridoxine. In primary hyperoxaluria type I, early diagnosis and pre-emptive isolated liver transplantation can be curative. In patients who already have advanced CKD (CKD stages 4 and 5), intensive dialysis therapy is appropriate. Concomitant liver and renal transplantation is often performed, but in this situation the renal transplants can be lost due to rapid oxalate crystal deposition (prior liver transplantation is preferable because it would allow clearance of the oxalate load before consideration of renal transplantation). 13.1.6 Phenylketonuria There are several variants of phenylketonuria (PKU) due to different allelic mutations. For example, mutations of the gene that encodes phenylalanine hydroxylase (and associated enzymes) are found on chromosome 12. Only severe deficiency of the enzyme results in classic PKU with neurological damage. PKU affects between 1/10 000 and 1/14 000 live births. The biochemical abnormality is an inability to convert phenylalanine into tyrosine due to lack of phenylalanine hydroxylase. This results in hyperphenylalaninaemia and increased excretion of its metabolite, phenylpyruvic acid (‘phenylketone’) in the urine. Clinical features of PKU • • • • • Affects children, usually manifesting by 6 months of life Irritability Decreased pigmentationa (pale skin, fair-haired and blue-eyed phenotype) Eczema Learning disability aThis is due to reduced melanin formation. Diagnosis The Guthrie screening test is a neonatal blood test taken from a heel prick. Phenylalanine levels are measured by spectrofluorometric methods or using a form of mass spectrometry that has the ability to analyse many amino acids, fatty acids and shortchain organic acid metabolites simultaneously. Management A diet low in phenylalanine, with tyrosine supplementation in infancy and childhood, is now also recommended for adults. Commencing the diet as soon as possible after birth can prevent the deleterious consequences, which are irreversible. PKU females should be advised to reinstitute strict dietary control before conception and throughout pregnancy and breastfeeding. Fish oil supplementation can also improve symptoms. 13.2 DISORDERS OF PURINE METABOLISM Uric acid is the end product of purine metabolism. Purines can be synthesised new or salvaged from the breakdown of nucleic acids of endogenous or exogenous origin. Increased new synthesis of purines is thought to be responsible, at least partly, for primary gout. Deficiency of hypoxanthine– guanine phosphoribosyl transferase (HGPRT), which is involved in the salvage pathway, results in the Lesch–Nyhan syndrome. Disorders of purine metabolism • Primary gout • Lesch–Nyhan syndrome • Secondary hyperuricaemia (See also Chapter 20, Rheumatology.) 13.2.1 Gout More than 10% of the population of the western world has hyperuricaemia, which can be due to a variety of genetic and environmental factors. Gout develops in less than 0.5% of the population. (See also Chapter 20, Rheumatology.) • • • • • • • Primary hyperuricaemia is more common in males and postmenopausal females than in premenopausal females It is rare in childhood It is probably polygenic, involving both increased purine synthesis and reduced renal tubular secretion of urate Gout can be precipitated by thiazide diuretics, alcohol and high purine (meat) intake Treatment is with non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine for acute episodes. NSAIDS or colchicine may be contraindicated or poorly tolerated by some groups of patients (eg CKD); short courses of oral steroids, or a long-acting intramuscular steroid injection, can be prescribed as an alternative. Longer-term lowering of uric acid is achieved with allopurinol. The selective nonpurine xanthine oxidase inhibitor febuxostat has also been shown to effectively lower serum uric acid levels Hyperuricaemia is associated with increased cardiovascular risk Hyperuricaemia is also a sensitive marker for pre-eclampsia. Elevated levels correlate with maternal and fetal mortality and morbidity. 13.2.2 Lesch–Nyhan syndrome Lesch–Nyhan syndrome is an uncommon X-linked recessive disease (therefore seen only in males) due to complete lack of hypoxanthine–guanine phosphoribosyl transferase (HaPRT). This results in accumulation of both hypoxanthine and guanine, both of which are metabolised to xanthine and subsequently to uric acid. Clinical features of Lesch–Nyhan syndrome • Neurological disability, eg dystonia, choreoathetosis • Self-injurious behaviour which can be severe • Learning disability • Renal calculi • Gout and gouty arthritis • CKD due to crystal nephropathy Neurological manifestations are usually present in early infancy and consequently patients • present with delayed motor development. Patients rarely survive beyond the age of 40. This is usually due to end-stage renal disease or aspiration pneumonia Kelley–Seegmiller syndrome is a variant, with mild neurological symptoms, due to a partial • deficiency of HaPRT Treatment of the uric acid overproduction is with allopurinol or febuxostat. Treatments for the neurological and behavioural symptoms are limited mutation detection and linkage analysis for • probands and their families. Biochemical measurement of HaPRT enzyme activity is also possible for at-risk pregnancies. 13.3 DISORDERS OF METALS AND METALLOPROTEINS Iron and copper play central roles in the function of a number of metalloproteins, including cytochrome oxidase, which is essential in cellular aerobic respiration; haem, based on iron, is the key molecule in oxygen transport. Excessive accumulation can, however, promote free radical injury (eg Wilson’s disease and haemochromatosis) and disorders of haem synthesis result in porphyria. Disorders of metals and metalloproteins • • • • Wilson’s disease Secondary iron overload Haemochromatosis The porphyrias 13.3.1 Wilson’s disease This autosomal recessive disorder has a gene frequency of 1/400 and a disease prevalence of approximately 1/200 000. The responsible defective gene (ATP 7B) is on chromosome 13, and this codes for a copper-transporting P-type adenosine triphosphate. In normal individuals 50% of ingested copper is absorbed and transported to the liver loosely bound to albumin. Here copper is incorporated into an α2-globulin to form ceruloplasmin, which is the principal transport protein for copper, and necessary for biliary excretion. In Wilson’s disease copper absorption is normal but intrahepatic formation of ceruloplasmin is defective. Total body and tissue copper levels rise due to failure of biliary excretion and urinary excretion of copper is increased. Clinical features of Wilson’s disease • • • • • • • • Onset in childhood or adolescence Hepatic dysfunction • Acute hepatitis • Cirrhosis (most common) • Chronic hepatitis • Massive hepatic necrosis Hypoparathyroidism Haemolysis Neuropsychiatric disturbance (often presents later than hepatic dysfunction) • Slurred speech, ataxia, chorea, seizures • Subcortical dementia • Frontal lobe impairment resulting in personality change • Psychosis, anxiety and depression Kayser–Fleischer corneal rings (asymptomatic) • Due to copper deposition in Descemet’s membrane Fanconi syndrome Musculoskeletal • Degenerative arthropathy resembling premature osteoarthritis • Osteopenia (50%) • Osteoporosis • Chondrocalcinosis Diagnosis Wilson’s disease should be considered in any patient with unexplained hepatic dysfunction and neurological/neuropsychiatric symptoms. Diagnosis is based on a decrease in serum ceruloplasmin and increases in hepatic copper content and urinary excretion of copper. However, biochemical diagnosis is increasingly recognised to have low sensitivity. Molecular diagnosis is available to identify presymptomatic individuals. Serum copper levels are of no diagnostic value. Liver biopsy is also used to facilitate diagnosis. Management Early detection permits lifelong use of medications that can prevent the deleterious effects of copper accumulation. Copper chelators (eg penicillamine and trientine) are used to remove copper in symptomatic patients. In patients who have no symptoms, zinc is used to prevent the build-up of copper. Zinc works by preventing copper absorption in the gut. It is also used in patients who have responded to treatment with chelators as maintenance therapy. Fulminant hepatic failure and end-stage liver disease necessitate liver transplantation, which is curative (but CNS sequelae may persist). First-degree relatives should be screened for Wilson’s disease. (See also Chapter 6, Gastroenterology.) 13.3.2 Haemochromatosis In the normal adult the iron content of the body is closely regulated. Haemochromatosis is the excessive accumulation of iron. Primary (or idiopathic) haemochromatosis is a common autosomal recessive disorder in which iron accumulates in parenchymal cells, leading to damage and fibrosis. Haemosiderin is an insoluble iron–protein complex found in macrophages (it is relatively harmless to them) in the bone marrow, liver and spleen. Secondary iron overload, which has many causes, is often referred to as ‘haemosiderosis’. The gene for haemochromatosis (HFE) is located on chromosome 6 close to the HLA locus. HFE codes for a transmembrane glycoprotein that modulates iron uptake. Over 85% of white patients are homozygous for the HFE C282Y mutation. The gene frequency is 6% and disease frequency 1/220 people, but the severity of the disease seems to vary. The disease is therefore staged as follows: • Stage 1: genetic disorder with no increase in iron stores in those who have genetic susceptibility Stage 2: genetic disorder in those who have phenotypic evidence of iron overload but no tissue • or organ damage Stage 3: genetic disorder with iron overload and iron deposition resulting in tissue and organ • damage. Diagnosis Serum iron is elevated with >45% transferrin saturation. Serum ferritin is >500 μg/L, but it is important to note that the most common causes of elevated ferritin (an acute phase reactant) are inflammation, alcohol and many other conditions. The combination of elevated transferrin saturation and ferritin in a patient with a family history or clinical features of haemochromatosis should prompt molecular genetic diagnosis for an HFE mutation. Liver iron concentration >180 μmol/g is also indicative of haemochromatosis. Management • • • • Venesection to maintain ferritin between 50 and 100 μg/L Chelation therapy with desferrioxamine if unable to undergo venesection Avoid vitamin C supplements as they enhance iron absorption Screening of first-degree relatives (serum ferritin) Screening cirrhotic patients for hepatocellular carcinoma is recommended (6-monthly ultrasound • and serum α-fetoprotein) • Liver transplantation (for end-stage liver disease). 13.3.3 Secondary iron overload Secondary haemochromatosis is due to iron overload, which can occur in a variety of conditions. The pattern of tissue injury is similar to that in primary haemochromatosis. In the inherited haemolytic anaemias, iron overload can present in adolescence; the features are often modified by the underlying disease. Treatment is with desferrioxamine. Secondary causes of iron overload • • • • • Anaemia due to ineffective erythropoiesis • β-Thalassaemia • Sideroblastic anaemia • Aplastic anaemia • Pyruvate kinase deficiency Parenteral iron overload • Blood transfusions • Iron transfusions Liver disease • Alcoholic cirrhosis • Chronic viral hepatitis • Porphyria cutanea tarda Increased oral iron intake (Bantu siderosis) Congenital transferrinaemia 13.3.4 The porphyrias The porphyrias are a rare heterogeneous group of conditions caused by abnormalities of enzymes involved in the biosynthesis of haem, resulting in overproduction of the intermediate compounds called porphyrins. Most porphyrias are hereditary, although some can be acquired. Excess production of porphyrins can occur in the liver or bone marrow and is classified as acute or non-acute. The haem metabolic pathway and the type of porphyria resulting from different enzyme deficiencies are shown in Figure 13.1. The two most important porphyrias are porphyria cutanea tarda and acute intermittent porphyria – these are described in more detail. Porphyria cutanea tarda This is the most common hepatic porphyria. There is a genetic predisposition but the pattern of inheritance is not established. It is more common in men and usually presents after the age of 40. Many sporadic cases are due to chronic liver disease, usually alcohol-related. • There is reduced uroporphyrinogen decarboxylase activity • Uroporphyrinogen accumulates in blood and urine Manifests as photosensitivity rash with bullae. Porphyrins produce free radicals when exposed • to ultraviolet light which results in damage to sun-exposed skin. Diagnosis Based on elevated urinary uroporphyrinogen (urine is normal in colour). Treatment • The underlying liver disease • Venesection • Low-dose chloroquine – used infrequently to mobilise porphyrins from the liver. Acute intermittent porphyria This causes attacks of classic acute porphyria, often presenting with abdominal pain and/or neuropsychiatric disorders. It is an autosomal dominant disorder. Figure 13.1 Haem synthesis and the porphyrias • • • • • • There is reduced hepatic porphobilinogen deaminase activity The gene (and disease) frequency is between 1/10 000 and 1/50 000 Episodes of porphyria are more common in females There is no photosensitivity or skin rash There is increased urinary porphobilinogen and aminolaevulinic acid, especially during attacks Urine turns deep red on standing. Clinical features of acute intermittent porphyria • • • • • • • Onset in adolescence Abdominal pain occurs in 95% of acute episodes, vomiting, constipation Neuropsychiatric disorders Episodic attacks Polyneuropathy (motor) Hypertension and tachycardia Tubulointerstitial nephritis Precipitating drugs: • • • • • • Alcohol Benzodiazepines Rifampicin Oral contraceptives Phenytoin Sulfonamides. Other precipitating factors: • • • • • Stress Pregnancy Changes in the menstrual cycle (especially premenstrual) Infection Fasting. Management • Supportive: maintain high carbohydrate intake; avoid precipitating factors • Early detection of the signs and symptoms of an acute episode Acute episodes are treated with daily haem arginate infusions for 3–4 days as well as • treatment/withdrawal of any precipitating agents • Of patients, 10% die as a result of hepatocellular carcinoma. 13.4 DISORDERS OF LIPID METABOLISM Hyperlipidaemia, especially hypercholesterolaemia, is associated with cardiovascular disease (Table 13.1). Table 13.1 Cholesterol level and relative risk of myocardial infarct Total cholesterol (mmol/L) Relative risk of myocardial infarct 5.2 6.5 7.8 1 2 4 Although lipid metabolism is complex, and many inherited or acquired disorders can disrupt it, the end result is usually elevated cholesterol and/or triglyceride concentrations. These can be managed by dietary and pharmacological means. 13.4.1 Lipid metabolism Cholesterol and triglycerides are insoluble in plasma and circulate bound to lipoproteins. The lipoproteins consist of lipids, phospholipids and proteins. The protein components of lipoproteins are called apolipoproteins (or apoproteins) and they act as cofactors for enzymes and ligands for receptors. Figure 13.2 is a schema of lipoprotein structure and lipid metabolism is shown in Figure 13.3. Figure 13.2 Schema of lipoprotein structure There are four major lipoproteins: Chylomicrons: large particles that carry dietary lipid (mainly triglycerides) from the • gastrointestinal tract to the liver. In the portal circulation, lipoprotein lipase acts on chylomicrons to release free fatty acids for energy metabolism Very-low-density lipoprotein (VLDL): carries endogenous triglyceride (60%), and to a lesser extent cholesterol (20%), from the liver to the tissues. The triglyceride core of the VLDL is also • hydrolysed by lipoprotein lipase to release free fatty acids. The VLDL remnants are called intermediate-density lipoprotein (IDL) Figure 13.3 Lipid metabolism Low-density lipoprotein (LDL): formed from the IDLs by hepatic lipase. LDL contains a • cholesterol core (50%) and lesser amounts of triglyceride (10%). LDL metabolism is regulated by cellular cholesterol requirements via negative feedback control of the LDL receptor High-density lipoprotein (HDL): carries cholesterol from the tissues back to the liver. HDL is formed in the liver and gut and acquires free cholesterol from the intracellular pools. Within the • HDL, cholesterol is esterified by lecithin cholesterol acyltransferase (LCAT). HDL is inversely associated with ischaemic heart disease. The LDL receptor Circulating LDL is taken up by the LDL receptor. Cells replete in cholesterol reduce LDL-receptor expression. In contrast, inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that controls the rate of new cholesterol synthesis, leads to a fall in cellular cholesterol and an increase in LDL-receptor expression. Lipoprotein (a) Lp(a) is a specialised form of LDL. Lp(a) inhibits fibrinolysis and promotes atherosclerotic plaque formation. It is an independent risk factor for ischaemic heart disease. 13.4.2 The hyperlipidaemias Population studies have consistently demonstrated a strong relationship between both total and LDLcholesterol and coronary heart disease. HDL is protective. A total cholesterol:HDL ratio >4.5 is associated with an increased risk. Intervention trials (eg the Cholesterol Treatment Trialists’ [CTT] Collaborators) have shown that a reduction of LDL cholesterol of 1 mmol reduces cardiovascular events by 21% and reduces the mortality rate by 12%. Triglycerides are also associated with cardiovascular risk; very high triglyceride levels are also associated with pancreatitis, lipaemic serum and eruptive xanthomas. Triglycerides must be measured fasting. A genetic classification of lipid disorders has now replaced the Fredrickson (WHO) classification, which was based on lipoprotein patterns. The primary hyperlipidaemias can be grouped according to the simple lipid profile. Secondary causes of hyperlipidaemia need to be excluded and are discussed below. Primary hypercholesterolaemia (without hypertriglyceridaemia) Familial hypercholesterolaemia (FH) is a monogenic disorder resulting from LDL-receptor dysfunction. A definitive diagnosis of FH is made using the Simon Broome criteria: Tendon xanthomas in a patient or a first-degree relative (parent, sibling, child), or in a second1. degree relative (grandparent, uncle, aunt), and elevated cholesterol concentrations as defined below: Child/young person Adult 2. • • • • • Total cholesterol (mmol/L) LDL-C (mmol/L) >6.7 >7.5 >4.0 >4.9 DNA-based evidence of an LDL-receptor mutation, familial defective Apo B100, or a PCSK9 mutation There are many different mutations in different families, all resulting in LDL-receptor deficiency/dysfunction and producing isolated hypercholesterolaemia Heterozygote prevalence is 1/500; homozygous FH is rare Other typical clinical features are Achilles tendon xanthomas (can also occur in other extensor tendons) and xanthelasma All patients with FH should have lipid-lowering therapy titrated upwards until there has been at least a 50% reduction in LDL-cholesterol Untreated FH results in coronary heart disease in 50% of men by the age of 50 and 30% of women by the age of 60. LDL-lowering apheresis (plasma exchange) LDL apheresis can lower plasma LDL by up to 65% after each treatment. This procedure involves the extracorporeal removal of LDL in a process similar to dialysis. The treatment is lifelong and performed weekly to fortnightly. It can be used to lower LDL-cholesterol in homozygous FH patients who have not responded to drug treatment or have evidence of coronary heart disease. It can also be used in exceptional cases for patients with heterozygous FH, ie progressive coronary heart disease despite maximal medical and surgical intervention. ACE inhibitors should not be used in patients undergoing LDL apheresis due to the increased risk of anaphylaxis. Liver transplantation Patients who have had maximal medical treatment and LDL apheresis can be considered for liver transplantation. The new liver provides functionally normal LDL receptors, thereby reducing plasma cholesterol levels In polygenic hypercholesterolaemia, the precise nature of the metabolic defect(s) is unknown. These individuals represent the right-hand tail of the normal cholesterol distribution. They are at risk of premature atherosclerosis. Depressed HDL levels are a risk factor for vascular disease. Factors modifying HDL levels • • Decreasing • Familial deficiency of HDL • Hyperandrogenic state • Post-pubertal males • Obesity • Hypertriglyceridaemia • Diabetes mellitus • Sedentary states • Cigarette smoking Increasing • Familial hyper-α-lipoproteinaemia • Low triglyceride levels • Thin habitus • Exercise • Oestrogens • Alcohol Primary hypertriglyceridaemia (without hypercholesterolaemia) Polygenic hypertriglyceridaemia is analogous to polygenic hypercholesterolaemia. Some cases are familial but the precise defect is not known. There is elevated VLDL Lipoprotein lipase deficiency and apoprotein CII deficiency are both rare. They result in • elevated triglycerides due to a failure to metabolise chylomicrons These patients present in childhood with eruptive xanthomas, lipaemia retinalis, retinal vein • thrombosis, pancreatitis and hepatosplenomegaly • Chylomicrons can be detected in fasting plasma. • Primary mixed (or combined) hyperlipidaemia • Familial polygenic combined hyperlipidaemia results in elevated cholesterol and triglycerides • The prevalence is 1/200 • There is premature atherosclerosis Remnant hyperlipidaemia is a rare cause of mixed hyperlipidaemia (palmar xanthomas and • tuberous xanthomas over the knees and elbows are characteristic). It is associated with apoprotein E2: There is a high cardiovascular risk. Secondary hyperlipidaemias are usually mixed, but either elevated cholesterol or triglycerides may predominate. Causes of secondary hyperlipidaemias • • Predominantly increased triglycerides • Alcoholism • Obesity • CKD • Diabetes mellitus • Liver disease • High-dose oestrogens Predominantly increased cholesterol • Hypothyroidism • Renal transplant • Cigarette smokinga • Nephrotic syndrome • Cholestasis aCigarette smoking reduces HDL. 13.4.3 Lipid-lowering drugs Cholesterol and triglyceride levels should be considered in combination with other risk factors (also see Chapter 1, Cardiology). Potential secondary causes of hyperlipidaemia should be corrected. Dietary intervention can be expected to reduce serum cholesterol by a maximum of 30%. Dietary measures should be continued with pharmacological therapy. Table 13.2 shows the impact that can be expected with the various agents. The side-effect profile of the older agents made them unpopular and reduced compliance. In most cases, hypercholesterolaemia will respond to dietary intervention and statin therapy; and mixed or isolated hypertriglyceridaemia, to diet and a fibrate. Treatment of hyperlipidaemia can reduce the risk of coronary heart disease by 30%. The side-effects and interactions of lipid-lowering drugs are given in Table 13.3. HMG-CoA reductase inhibitors (statins) Statins are widely used to lower cholesterol and have been shown to reduce cardiovascular events. Simvastatin is now available in a generic formulation; consequently many patients are having their current statin treatment ‘switched’ to simvastatin on the assumption that all statins are the same, which they are not. While switching patients to generic simvastatin is more often than not complication free, care should be taken to avoid potential drug interactions, eg protease inhibitors used in antiretroviral regimens inhibit the metabolism of simvastatin and are contraindicated. However, protease inhibitors do not interact with atorvastatin or pravastatin. Table 13.2 Impact of lipid-lowering drugs Drug class HMG-CoA reductase inhibitors Fibrates Ezetimibe Sterols and stanols Anion-exchange resins Nicotinic acid Probucol Neomycin Fish oil ↓LDL (%) ↑HDL (%) ↓TGs (%) 20–40 5–10 10–20 10–15 15–20 10–20 15–30 10–25 10–15 20–25 5–10 15–25 No change No change No change 15–35 ↓20–25 No change No change 35–50 No change No change No change 25–30 No change No change 30–50 HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; TGs, triglycerides. Table 13.3 Side-effects and drug interactions of lipid-lowering drugs Drug class Side effects/interactions HMG-CoA reductase inhibitors Simvastatin (but not pravastatin) potentiates warfarin and digoxin Increased risk of myopathy with a number of drugs including amlodipine and diltiazem Fibrates Gemfibrozil Bezafibrate Potentiates warfarin. Gemfibrozil absorption is impaired by anionexchange resins Ezetimibe Headache, abdominal discomfort. Rarely, hypersensitivity, thrombocytopenia, myositis, pancreatitis and abnormal LFTs Sterols and stanols Well tolerated as naturally occurring substances but may cause lower GI symptoms: diarrhoea, constipation Anion-exchange resins (aka bile acid sequestrants) Cholestyramine Cholestipol GI side-effects: nausea, cramping, abnormal LFTs Impaired absorption of digoxin, warfarin, thyroxine and fat-soluble vitamins Nicotinic acid Flushing, headaches, upper GI symptoms, acanthosis nigricans and myositis Probucol Diarrhoea, eosinophilia, long QT syndrome, angioneurotic oedema Neomycin Ototoxicity, nephrotoxicity Fish oil Halitosis, bloating, nausea Impaired glycaemic control in type 2 diabetes mellitus GI, gastrointestinal; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LFTs, liver function tests. Current UK guidelines recommend that cardiovascular risk should be estimated using the Framingham 1991 10-year risk equation. However the Framingham risk equation was developed from North American patients and consequently they have been shown to overestimate cardiovascular risk in northern European populations by up to 50% and underestimate cardiovascular risk in patients who are socially deprived. Alternative risk equations are available, eg QRISK (UK), ASSIGN (Scotland). The QRISK equations have been developed using data from the UK population. Published data suggest QRISK equations may be better predictors of cardiovascular events than the Framingham equation in the UK. The QRISK equations take family history and social deprivation into consideration. These equations are currently in evolution and it is likely that future guidelines will use QRISK or similar equations to calculate cardiovascular risk in England and Wales. Ezetimibe Ezetimibe selectively inhibits intestinal absorption of cholesterol. It is indicated for patients with primary hypercholesterolaemia who are intolerant of statins or when there is a contraindication to statin use. Sterols and stanols, eg Flora Pro-active Benecol These substances inhibit cholesterol absorption in the gut and thereby lower LDL-cholesterol. They are found naturally in a number of foods including extra virgin olive oil. They have no effect on HDLcholesterol or triglycerides. Sterols and stanols are being increasingly used commercially as an additive to margarines. Although studies have shown a reduction in LDL-cholesterol, further research is required to show whether this translates into a reduction in cardiovascular events. Secondary prevention It is recommended that all patients with established cardiovascular disease should be treated with a statin as first-line agent If total cholesterol is >4 mmol/L or LDL remains >2 mmol/L, statin treatment should be titrated • upwards. • 13.4.4 Rare lipid disorders A multitude of rare inborn errors of lipid metabolism can lead to multisystem diseases. The most common (all very rare) are shown in Table 13.4. Table 13.4 Rare inborn errors of lipid metabolism Disorder Serum lipid abnormality Clinical features Low cholesterol Low triglycerides Onset in childhood Fat malabsorption Acanthocytosis (of RBCs) Retinitis pigmentosa Ataxia and peripheral neuropathy Tangier’s disease Low cholesterol Onset in childhood Large orange tonsils Polyneuropathy No increased IHD risk LCAT deficiency ↑Triglycerides Variable cholesterol Affects young adults CKD Cerebrotendinous xanthomatosis None Affects young adults Cerebellar ataxia Dementia, cataracts Tendon xanthomas β-Sitosterolaemia None Affects adults Fabry’s disease None Abetalipoproteinaemia Affects young male adults (mild disease in females) Angiokeratomas Periodic crises Thrombotic events CKD Adrenoleukodystrophy None (ALD) Children >2 years Addison’s disease and progressive brain damage Adrenomyel oneuropathy A milder form of ALD that can be seen in men in their 20s and 30s. Presentation is similar to multiple sclerosis Disorder Pathogenesis Treatment Abetalipoproteinaemia Defective apoB synthesis Vitamin E Tangier’s disease Increased apoA catabolism None LCAT deficiency Reduced LCAT activity Low-fat diet Cerebrotendinous xanthomatosis Not known None β-Sitosterolaemia Increased sitosterol absorption Low plant-fat diet Fabry’s disease Deficiency of α-galactosidase A X-linked recessive Adrenoleukodystrophy (ALD) Human recombinant α-galactosidase A therapy Renal replacement therapy if endstage renal failure develops Lorenzo’s oil (a combination of oleic acid and euric acid) can reduce or delay symptoms X-linked Accumulation of very long-chain fatty acids (VLCFAs) in the brain and adrenal cortex Restrict dietary VLCFA intake Hormone replacement for adrenal insufficiency Adrenomyeloneuropathy CKD, chronic kidney disease; LCAT, lecithin–cholesterol acyltransferase; RBCs, red blood cells. IHD, ischaemic heart disease. 13.5 DISORDERS OF INORGANIC IONS BONE, MINERAL METABOLISM AND Bone is a unique type of connective tissue that mineralises. Biochemically it is composed of matrix (35%) and inorganic calcium hydroxyapatite (65%). Bone and mineral homeostasis are tightly regulated by numerous factors, so as to maintain skeletal integrity and control plasma levels. 13.5.1 Calcium homeostasis Calcium homeostasis is linked to phosphate homeostasis to maintain a balanced calcium phosphate product. Hypocalcaemia activates parathyroid hormone (PTH) release to restore serum ionised calcium; other stimuli to PTH release include hyperphosphataemia and decreased vitamin D levels • Hypercalcaemia switches off PTH release • Vitamin D promotes calcium and phosphate absorption from the gastrointestinal (GI) tract • • Bone stores of calcium buffer the serum changes. The metabolism and effects of vitamin D, and the actions of PTH, are shown schematically in Figures 13.4 and 13.5. 13.5.2 Hypercalcaemia In over 90% of cases hypercalcaemia is due to either hyperparathyroidism or malignancy. Hypercalcaemia normally suppresses PTH and so PTH is therefore the best first test to identity the cause of hypercalcaemia – if it is detectable (in or above the normal range) the patient must have hyperparathyroidism. • Primary hyperparathyroidism is common, especially in women aged 40–60 years. It is usually due to an adenoma of one of the four parathyroid glands Figure 13.4 Metabolism and the actions of vitamin D Figure 13.5 Control and actions of parathyroid hormone (PTH) • PTH-related protein (PTH-rP) is responsible for up to 80% of hypercalcaemia in malignancy PTH-rP acts on the same receptors as PTH and shares the first (N-terminal) 13 amino acids with • PTH; however, they are coded from two separate genes • Common malignancies secreting PTH-rP are squamous cell tumours, breast and kidney. Causes of hypercalcaemia • • • Increased calcium absorption • Increased calcium intake • Increased vitamin D Increased bone reabsorption • Primary and tertiary hyperparathyroidism • Malignancy • Hyperthyroidism Miscellaneous unusual causes • Lithium • Thiazide diuretics • Addison’s disease • Sarcoidosisa • Phaeochromocytoma • Familial hypocalciuric hypocalcaemiab • Theophylline toxicity • Milk-alkali syndromec • Vitamin A toxicity (rarely) aSarcoidosis causes hypercalcaemia due to excess production of 1,25-vitamin D by macrophages in the sarcoid lesions. 3 bFamilial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant condition. Most cases of FHH are a result of mutations in the calcium-sensing receptor. Patients are often incorrectly diagnosed with primary hyperparathyroidism. In contrast to primary hyperparathyroidism, FHH does not require any treatment. cHypercalcaemia can be seen in patients who consume excess quantities of Rennies bought over the counter. The symptoms of hypercalcaemia are often mild but a range of manifestations can occur. The mnemonic ‘stones, bones, abdominal groans and psychic moans’ can be used to describe these symptoms. Clinical manifestations of hypercalcaemia • • • • • • • • • • • • • • Malaise/depression Lethargy Muscle weakness Confusion Peptic ulcerationa Pancreatitis Constipation Nephrolithiasis Nephrogenic diabetes insipidus Distal renal tubular acidosis (RTA) CKDb Short QT syndrome Band keratopathy Diabetes insipidus aPeptic ulceration is due to excess gastrin secretion. bCKD is due to chronic tubulointerstitial calcification and fibrosis. The management of acute hypercalcaemia (serum calcium >3 mmol/L) involves: • Adequate rehydration – 3–4 L saline/day • Intravenous bisphosphonates (eg pamidronate disodium) Identification of the cause, and its subsequent specific treatment (eg corticosteroids for sarcoid) • if indicated. 13.5.3 Hyperparathyroid bone disease Hyperparathyroidism has a prevalence of about 1/1000. It results in bone reabsorption due to excess PTH action. Primary hyperparathyroidism is caused by a single (80+%) or multiple (5%) parathyroid adenomas or by hyperplasia (10%). Parathyroid carcinoma is rare (<2%). It results from abnormal regulation of PTH by calcium because of an increase in the calcium set point. Familial cases (as seen in multiple endocrine neoplasia [MEN] type 1) have a higher incidence of hyperplasia and, similar to parathyroid carcinoma, can be associated with abnormalities of chromosome 11 (usually deletions in the little q13 region). Biochemically there is increased PTH, serum and urinary calcium, reduced serum phosphate and increased alkaline phosphatase. Histologically there is an increase of both osteoblasts and osteoclasts resulting in ‘woven’ osteoid, increased resorption cavities (‘osteitis fibrosa cystica’) and marrow fibrosis. The definitive treatment of primary hyperparathyroidism is by surgical parathyroidectomy. Secondary hyperparathyroidism is physiological compensatory hypertrophy of all four glands due to hypocalcaemia (eg CKD, malabsorption). PTH levels are raised; calcium is low or normal. The secondary hyperparathyroidism in CKD is controlled by phosphate restriction, phosphate binders and with use of 1α-hydroxylated vitamin D preparations (see also Chapter 15, Nephrology). Cinacalcet is a calcimimetic that acts on calcium-sensing receptors to increase receptor sensitivity to calcium, which in turn results in a decrease in PTH. Cinacalcet is licensed for the treatment of advanced secondary hyperparathyroidism.a Tertiary hyperparathyroidism is the development of autonomous parathyroid hyperplasia in the setting of long-standing secondary hyperparathyroidism – usually in CKD. Calcium levels are raised. Treatment is in the form of parathyroidectomy or cinacalcet.a 13.5.4 Hypocalcaemia Hypocalcaemia is usually secondary to CKD (increased serum phosphate), hypoparathyroidism or vitamin D deficiency. Causes of hypocalcaemia • • • Decreased calcium absorption • Hypoparathyroidism • Hypovitaminosis D • Malabsorption • Sepsis • Fluoride poisoning • Hypomagnesaemiaa Acute respiratory alkalosis Hyperphosphataemia (by reduction in ionised calcium) • CKD • Phosphate administration • Rhabdomyolysis • • Tumour lysis syndrome Deposition of calcium • Pancreatitis • Hungry bone syndrome • EDTA infusion • Rapidly growing osteoblastic metastases aCause of functional hypoparathyroidism. Hypoparathyroidism can be spontaneous (autoimmune), post-surgical or due to a receptor defect (pseudohypoparathyroidism). Autoimmune hypoparathyroidism may be part of autoimmune polyglandular failure type I (mucocutaneous candidiasis, with adrenal, gonadal and thyroid failure). Treatment is with calcium and vitamin D supplements. Recombinant human 1–34-PTH (teriparatide) is available but is not used in clinical practice for hypoparathyroidism because of its cost, need for parenteral administration and short half-life. It has been used for post-surgical hypoparathyroidism over a short-term period, but it is more routinely used in the management of osteoporosis. In pseudohypoparathyroidism there is a characteristic phenotype with short stature, short metacarpals and intellectual impairment. The disorder is due to a G-protein abnormality (see Chapter 14, Molecular medicine). Vitamin D deficiency can occur in several settings, including: • • • • • Dietary deficiency/lack of sunlight Malabsorption CKD (failure of 1α-hydroxylation) 1α-hydroxylase deficiency (vitamin D-dependent rickets type I) Vitamin D-receptor defect (vitamin D-dependent rickets type II). Rickets without vitamin D deficiency and with normal calcium may be due to hypophosphataemia, as in X-linked dominant, hypophosphataemic, vitamin D-resistant rickets. The symptoms of hypocalcaemia are mainly those of neuromuscular irritability and neuropsychiatric manifestations. Signs include Chvostek’s sign (tapping the facial nerve causes twitching) and Trousseau’s sign (precipitation of tetanic [carpopedal] spasm in the hand by sphygmomanometerinduced ischaemia). Trousseau’s sign is a more specific test for hypocalcaemia. The development of symptoms depends on how quickly the level of calcium falls as well as the serum concentration. Clinical manifestations of hypocalcaemia • Neuromuscular • Tetany • Seizures • • • • Confusion • Extrapyramidal signs • Papilloedema • Psychiatric • Myopathy • Prolonged QT syndrome Ectodermal • Alopecia • Brittle nails • Dry skin Cataracts Dental hypoplasia Table 13.5 lists the causes of hypocalcaemia and the related biochemical findings. The management of hypocalcaemia involves: • Intravenous calcium gluconate if severe (tetany/seizures) Table 13.5 Causes of hypocalcaemia – biochemical findings Cause Serum PTH Vitamin D levels Phosphate Alkaline phosphatase Hypoparathyroidism Vitamin D deficiency Pseudohypoparathyroidism CKD Low High High High Normal Low Normal Low High Low High High Normal High Normal High CKD, chronic kidney disease; PTH, parathyroid hormone. • Oral calcium supplements • Vitamin D (for hypoparathyroidism, vitamin D deficiency and CKD) Normalise serum magnesium levels Hypocalcaemia is difficult to correct if serum magnesium • levels are low • Thiazide diuretic and low-sodium diet. 13.5.5 Hypercalciuria Hypercalciuria is the most common cause of kidney stones and contributes to the development of osteoporosis. Hypercalciuria occurs as a result of excessive duodenal calcium absorption (normally the duodenum absorbs only 20% of ingested calcium), renal calcium leak or excessive bone absorption (eg hyperparathyroidism), resulting in excess serum calcium and subsequent hypercalciuria. Excessive calcium absorption is the most common cause of hypercalciuria, although the causes often overlap. Causes of hypercalciuria • • • • Absorptive • Excess calcium ingestion • Milk-alkali syndrome • Vitamin D excess • Sarcoidosisa Renal hypercalciuria (renal leak) • Medullary sponge kidney (30–50%) • Bartter syndromeb • Dent’s diseasec • Autosomal-dominant hypercalciuric hypocalcaemiad Resorptive • Hyperparathyroidism • MEN-1 (with hyperparathyroidism) Miscellaneous • Hyperthyroidism • Renal tubular acidosis • Prolonged immobilisation • Paget’s disease • Pregnancy aExcess 1,25-vitamin D production results in hypercalcaemia and hypercalciuria. 3 bRare autosomal recessive condition caused by mutations in the genes involved in the active absorption of chloride in the loop of Henle. This results in excess sodium and potassium loss in the urine. Secondary hyperaldosteronism occurs with hypokalaemic alkalosis. Blood pressure is usually normal. cAlso known as X-linked recessive hypophosphataemic rickets. dMutation in the calcium-sensing receptor. Investigations • 24-hour urinary calcium • Serum calcium, phosphate, creatinine and PTH Calcium loading test in patients who have not responded to dietary calcium restriction. Patients are fasted and then administered a calcium load. Urine calcium is checked at intermittent periods • to distinguish the cause of hypercalciuria, eg patients with renal leak hypercalciuria will not change the amount of calcium excreted, whereas patients with absorptive hypercalciuria will increase calcium excretion in response to the calcium load. Treatments • Most hypercalciuria can be managed with dietary calcium restrictions Reduce sodium intake (elevated sodium intake increases calcium excretion, raises urinary pH • and reduces urinary citrate excretion, thereby increasing stone formation) Thiazide diuretics are used in patients with renal leak or who have not responded to dietary • restriction alone. Thiazide diuretics reabsorb calcium in the renal tubule Bisphosphonate can be used in patients who have hypercalciuria as a result of excessive bone • resorption (especially patients with osteoporosis) Orthophosphates reduce hypercalciuria by reducing vitamin D3 levels and increasing tubular • reabsorption of calcium. Side-effects include GI disturbance. 13.5.6 Osteomalacia Osteomalacia (adults) or rickets (children) result from inadequate mineralisation of osteoid. The biochemical features are: elevated alkaline phosphatase (95%), hypocalcaemia (50%) and hypophosphataemia (25%). It is usually caused by a defect of vitamin D availability or metabolism. Approximately 1 billion people have osteomalacia worldwide. In the UK the prevalence increases with age, with a prevalence of 30% in the over-65s. Causes of osteomalacia • • • • Vitamin D deficiency • Dietarya • Sun exposureb • Malabsorption • Gastrectomy • Small-bowel disease • Pancreatic insufficiency Defective 25-hydroxylation • Liver disease • Anticonvulsant treatmentc Loss of vitamin D-binding protein • Nephrotic syndrome Defective 1α-hydroxylation • Hypoparathyroidism CKDd Defective target organ response • Vitamin D-dependent rickets (type II) Mineralisation defects • Abnormal matrix • Osteogenesis imperfecta • CKDd • Enzyme deficiencies • Hypophosphatasia Inhibitors of mineralisation • Fluoride • Aluminium • Bisphosphonates Phosphate deficiency • Decreased GI intake • Antacids (reduce absorption) • Impaired renal reabsorption • Fanconi syndrome • X-linked hypophosphataemic rickets (vitamin D-resistant rickets) • • • • • aVegans in particular may not benefit from dietary vitamin D. bAsian immigrants in western countries are at increased risk because melanin in skin decreases D formation and certain foods (eg 3 chapattis) bind calcium, unmasking vitamin D deficiency. cEspecially phenytoin. dPatients with CKD can have mixed bone disease where there is hyperparathyroid bone disease in combination with osteomalacia. The management of osteomalacia involves: • Diagnosis and treatment of the underlying disorder • Vitamin D therapy to correct hypocalcaemia and hypophosphataemia Beware iatrogenic hypercalcaemia when alkaline phosphatase begins to fall at the time of bone • healing. Oncogenic osteomalacia This is a paraneoplastic syndrome usually caused by benign tumours of mesenchymal origin. Patients have osteomalacia, bone pain, phosphaturia and hypophosphataemia. 13.5.7 Paget’s disease Paget’s disease is a focal (or multifocal) bone disorder characterised by accelerated and disorganised bone turnover resulting from increased numbers and activity of both osteoblasts and osteoclasts. A viral aetiology has not been confirmed. • Rare in patients aged <40 years Prevalence of 1–2% in white people aged >55 years. The UK has the highest prevalence (4.6%) • in Europe • Familial clustering and HLA linkages (15% have a positive family history) Biochemically characterised by raised alkaline phosphatase, osteocalcin and urinary • hydroxyproline excretion. Radiographs and radionuclide bone scans aid diagnosis • There is an increased risk of malignant transformation. Paget’s disease is usually diagnosed because of asymptomatic sclerotic changes (which can mimic sclerotic bone metastases) but a number of complications can arise. Clinical manifestations of Paget’s disease • • • • • • • • Bone pain Fractures (and pseudofractures) Secondary arthritis Neurological compression syndromesa Osteosarcoma (rare) High-output congestive cardiac failure Hypercalcaemia (only with immobilisation) Skeletal deformity aIncluding deafness, other cranial nerve palsies and spinal stenosis. Treatment is indicated for bone pain, nerve compression, disease impinging on joints and immobilisation hypercalcaemia. Options include: • Bisphosphonates • Calcitonin • Surgery. Causes of a raised bone alkaline phosphatase • • With high calcium • Hyperparathyroidism With high or normal calcium • Malignancy • Paget’s disease • • With normal calcium • Puberty • Fracture • Osteogenic sarcoma With low calcium • Osteomalacia 13.5.8 Osteoporosis A very common disorder characterised by reduced bone density and increased risk of fracture. The most common form is postmenopausal osteoporosis, which affects 50% of women aged 70. Common sites of fracture are the vertebrae, neck of femur (trabecular bone), and distal radius and humerus (cortical bone); these fractures can occur with minimal trauma. Diagnosis is by bone mineral densitometry, measured by dual-energy X-ray absorptiometry (DXA), single-photon absorptiometry (SPA) or quantitative computed tomography (QCT) (Table 13.6). The measured bone density is compared with the mean population peak bone density (ie that of young adults of the same sex) and expressed as the number of standard deviations from that mean, the T score. The bone mineralisation and serum biochemistry are normal. • T scores down to −1 are regarded as normal • T scores between −1 and −2.5 represent osteopenia • T scores below −2.5 are osteoporotic. Table 13.6 Comparison of DXA, SPA and QCT Method Measurements Pros and cons Cost DXA QCT Spine, hip, radius Spine, hip, radius ££ £££ E SPA Radius, calcaneum Most widely available Most accurate Better for patients with extensive osteoarthritis Increased radiation Expensive Not as accurate as DXA and QCT £ DXA, dual-energy X-ray absorptiometry; QCT, quantitative computed tomography; SPA, single-photon absorptiometry. Fracture risk The risk of future fractures is dependent on both bone quality (strength and resilience) and the risk of falling. Fractures increase twofold with each standard deviation of the T score and independently with age by 1.5-fold per decade. Aetiology From the age of 30, bone loss occurs at about 1% per year. This is accelerated to about 5% per year in the 5 years after the menopause. Persistent elevations of PTH will accelerate bone loss further. This occurs both in primary hyperparathyroidism but also in secondary hyperparathyroidism arising in vitamin D deficiency, or in negative calcium balance (eg hypocalcaemia, hypercalciuria). Aetiology of osteoporosis • • • Primary • Type 1: postmenopausal • Type 2: age-related or involutional • Osteoporosis of pregnancy Secondary Endocrine: premature menopause, Cushing syndrome, hypopituitarism, • hyperparathyroidism, prolactinomas, hypogonadism, hyperthyroidism • Drugs: steroids, heparin, ciclosporin, anticonvulsants • Malignancy: multiple myeloma, leukaemia • Inflammatory: rheumatoid arthritis, ulcerative colitis • GI: gastrectomy, malabsorption, primary biliary cirrhosis • CKD • Immobilisation, eg space flight Other: osteogenesis imperfecta, homocystinuria, Turner syndrome (oestrogen deficiency), • rheumatoid arthritis,a scurvy Additional risk factors for osteoporosis • Race: White/Asian • Short stature and low body mass index • Positive family history • Multiparity • Amenorrhoea >6 months (other than pregnancy) • Poor calcium and vitamin D intake • Excess alcohol and smoking aIn rheumatoid arthritis, osteoporosis is multifactorial but corticosteroids and immobility are major contributors. In the absence of a recent fracture or secondary cause of osteoporosis, bone biochemistry should be normal. Treatment of osteoporosis • • • General measures • Correct any secondary cause • Weight-bearing exercise • Adequate dietary calcium and vitamin D intake Specific drug treatments (These may reduce fractures by approximately 50%) • Bisphosphonatesa • Denosumab (novel human monoclonal antibody)b • Oestrogens (hormone replacement therapy [HRT]) • Calcium and vitamin D combination therapy • Testosterone (in males) • Selective oestrogen receptor modulators (SERMs), eg raloxifene • Teriparatide (1–34-PTH) • Strontium ranelate Other Fluoride (increases bone density, but reduces bone microstructure quality). Fluoride • accumulates in peripheral bone and increases the risk of microfractures (stress fractures) and fracture in peripheral weight-bearing bones • Calcitonin aProphylaxis with bisphosphonates is now recommended for patients receiving high-dose (eg relapsing nephrotic syndrome) or long-term (eg asthma) steroids. bDenosumab is a human monoclonal antibody against RANKL (receptor activator of nuclear factor kB ligand). RANKL is involved in bone resorption. 13.5.9 Disorders of magnesium Magnesium is principally found in bone (50–60%) as an intracellular cation and plasma levels are maintained within the range 0.7–1.1 mmol/L. It plays an important role in many metabolic pathways. Disorders of magnesium balance usually occur in association with other fluid and electrolyte disturbances, in particular calcium and potassium. Hypomagnesaemia Hypomagnesaemia is frequently accompanied by hypocalcaemia, hypophosphataemia and hypokalaemia. Patients are often asymptomatic but may complain of weakness or anorexia, and features of neuromuscular irritability have been described. Hypomagnesaemia is an important risk factor for ventricular arrhythmias. Causes of hypomagnesaemia • • • • • Gastrointestinal losses • Diarrhoea • Malabsorption • Small-bowel disease • Acute pancreatitisa Loop of Henle dysfunction • Acute tubular necrosisb • Renal transplantation • Post-obstructive diuresis • Bartter syndrome • Gitelman syndrome Renal losses • Loop and thiazide diuretics • Volume expansion • Alcoholc • Diabetic ketoacidosis • Hypercalcaemiad Nephrotoxins • Aminoglycosides • Amphotericin B • Cisplatin • Pentamidine • Ciclosporin Primary renal magnesium wastinge aDue to the formation of magnesium soaps in the areas of fat necrosis. bDiuretic phase. cAlcohol acutely increases urinary magnesium excretion; in chronic alcoholism this is compounded by ketoacidosis and phosphate depletion. dHypercalciuria increases magnesium excretion; if saline and diuretics are given to treat hypercalcaemia then the three stimuli together predispose to hypomagnesaemia. ePrimary magnesium wasting is a rare familial disorder. Hypermagnesaemia Hypermagnesaemia is rare. It is usually due to magnesium ingestion or infusion in the setting of CKD (ie when the kidney cannot excrete a magnesium load). • At concentrations >4 mmol/L symptoms develop, including lethargy, drowsiness, areflexia, paralysis, hypotension, heart block and finally cardiac arrest Toxic effects can be temporarily reversed by intravenous calcium (antagonises the neuromuscular and cardiac effects of hypomagnesaemia). In patients with normal renal function, intravenous • physiological saline with forced diuresis using loop diuretics can increase renal magnesium loss. Dialysis can also be used in patients with CKD or in severe hypermagnesaemia. Causes of hypermagnesaemia • • • • • • • • • • • CKD Adrenal insufficiency Magnesium infusion Milk-alkali syndrome Oral ingestion Lithium Magnesium enemas Theophylline intoxication Familial hypocalciuric hypercalcaemia Tumour lysis syndrome (release of intracellular magnesium) Rhabdomyolysis 13.5.10 Disorders of phosphate Serum phosphate is maintained between 0.8 and 1.4 mmol/L largely by renal regulation of excretion. Bone accommodates 85% of body stores; the rest is found extracellularly as inorganic phosphate and intracellularly as phosphate esters, eg phospholipids, nucleic acids and high-energy compounds such as adenosine triphosphate (ATP). Hypophosphataemia Hypophosphataemia can occur in a variety of settings, due to redistribution, renal losses or decreased intake. • Symptoms rarely develop unless phosphate <0.6 mmol/L; <0.3 mmol/L rhabdomyolysis likely Hypophosphataemia leads to reduced oxygen delivery (via reduced levels of 2,3• diphosphoglycerate [2,3-DPG]) and also impairs intracellular metabolism (by depleting ATP) Symptoms include weakness (especially respiratory muscles – a particular problem when • weaning certain ICU patients from respiratory support), confusion, coma, heart failure and rhabdomyolysis Fibroblast growth factor 23 (FGF-23) is phosphaturia. Patients with X-linked • hypophosphataemic rickets have very high levels of FGF-23 and marked phosphaturia. There is increasing research into the wider role of FGF-23 and phosphate metabolism. Causes of hypophosphataemia • • • Internal redistribution • Acute respiratory alkalosis • Hyperinsulinaemia • Post renal transplantation Decreased intestinal absorption • Inadequate intake (especially alcoholism, persistent vomiting) • Antacids containing aluminium or magnesium • Steatorrhoea and chronic diarrhoea Increased urinary excretion (phosphate wasting) • Primary and non-renal secondary hyperparathyroidism • Vitamin D deficiency/resistance • Fanconi syndrome • X-linked hypophosphataemic rickets • Miscellaneous – osmotic diuretics, thiazide diuretics • Acute volume expansion • Heavy metal poisoning • Oncogenic osteomalacia Treatment depends on the underlying condition and phosphate supplementation is commonly used. Vitamin D levels should be corrected. Hyperphosphataemia Hyperphosphataemia is common in acute and advanced CKD. It can also occur in massive tissue breakdown (eg rhabdomyolysis) and if there is increased tubular reabsorption of phosphate. It is usually asymptomatic. If symptoms do occur, they are secondary to a reduction in ionised calcium In acute hyperphosphataemia (with normal renal function), saline infusion to volume replete with • forced diuresis using a loop diuretic can be used to increase phosphate excretion In CKD a low-phosphate diet, phosphate binders and dialysis may be required. The high serum • phosphate in CKD is a major vascular risk factor in this population. • Causes of hyperphosphataemia • Massive acute phosphate load • Tumour lysis syndromea • Rhabdomyolysis • • • Lactic and ketoacidosis • Exogenous phosphate • Vitamin D intoxication CKD Increased tubular reabsorption of phosphate • Hypoparathyroidism • Pseudohypoparathyroidism • Severe hypomagnesaemia (results in PTH resistance) • Acromegaly • Thyrotoxicosis • Bisphosphonates aThe tumour lysis syndrome results in release of phosphate, potassium, purines (metabolised to uric acid) and proteins (metabolised to urea). It can result in acute kidney injury due to uric acid crystal deposition. 13.6 NUTRITIONAL AND VITAMIN DISORDERS In the developed countries, the most common nutritional problem is obesity (see also Chapter 4, Endocrinology). In contrast, in the developing countries, protein–energy malnutrition is common. In developed countries, the long-term sequelae of fetal and childhood undernutrition are increased cardiovascular disease in adult life. 13.6.1 The obesity and diabetes epidemic The World Health Organization (WHO) has also projected that the number of deaths attributable to diabetes will increase by 50% between 2005 and 2015. The increasing prevalence of obesity and its medical sequelae has become an increasing public health concern. Strategies to stem the epidemic are multifactorial and include: • Increase general population awareness of the impact of obesity Engage patients, local schools, workplaces and organisations in promoting healthier diets and • physical activity Consider referral to weight management programmes, and behavioural change strategies to • encourage physical activity and healthier diet choices • Drug treatments • Bariatric surgery. Clinical judgement should be used when interpreting body mass index (BMI), eg high muscle mass (Table 13.7). Asian patients may have increased risk factors at lower BMI. Waist circumference should also be used in patients with a BMI <35 kg/m2: Table 13.7 Classification of overweight and obesity Classification BMI (kg/m2) Healthy weight 18.5–24.9 Overweight 25–29.9 Obesity I 30–34.9 Obesity II 35–39.9 Obesity III ≥40 Treatment Drug treatment is recommended after dietary, exercise and behavioural strategies have been undertaken and assessed. Patients who have failed to reach their target weight or reached a plateau may benefit from drug treatment. There has been considerable interest in the development of antiobesity medication but at the time of writing, Orlistat remains the only drug recommended by the National Institute for Health and Care Excellence (NICE). Orlistat is an inhibitor of gastrointestinal and pancreatic lipase. It can reduce absorption of some fatsoluble vitamins and some medications. Side-effects include GI disturbance such as flatulence, diarrhoea and oily stools. Alternative short-term anti-obesity medications include CNS stimulants and appetite suppressants. Surgery is recommended in certain groups of patients and there are a number of different techniques available. A multidisciplinary team including the patient determines the choice of surgical technique. The box gives the NICE criteria for bariatric surgery. NICE criteria for bariatric surgery • BMI ≥40 kg/m2 2 2 • BMI between 35 kg/m and 40 kg/m and other significant disease (eg type 2 diabetes or high blood pressure) that could be improved if they lost weight All appropriate non-surgical measures have been tried but have failed to achieve or maintain • adequate, clinically beneficial weight loss for at least 6 months The person has been receiving or will receive intensive management in a specialist obesity • service • Medically fit for anaesthesia and surgery, and commits to the need for long-term follow-up Bariatric surgery is also recommended as a first-line option (instead of lifestyle interventions or • drug treatment) for adults with a BMI ≥50 kg/m2 in whom surgical intervention is considered appropriate Certain countries will also face a ‘double burden’ of disease. Middle-income countries (eg India) are seeing an increase in obesity in urban settings while still having to manage problems associated with undernutrition. 13.6.2 Protein–energy malnutrition Starvation is common in the developing world. In the developed countries, PEM frequently complicates severe sepsis, cachexia, liver cirrhosis, advanced CKD and malabsorption. In these circumstances undernutrition is a risk factor for death. Elderly people and in particular institutionalised individuals are at a markedly increased risk of malnutrition. Protein–energy malnutrition in both adults and children can be divided into undernutrition, kwashiorkor and marasmus (Table 13.8). Table 13.8 Wellcome Trust classification of protein–energy malnutrition Weight (% of standard for age) Oedema present Oedema absent 60–80 <60 Kwashiorkor* Marasmic kwashiorkor Undernutrition Marasmus *Kwashiorkor literally means ‘disease of the displaced child’. • Marasmus results from severe deficiency of both protein and calories • Kwashiorkor results primarily from protein deficiency (ie diet entirely of carbohydrate) Oedema is the cardinal sign separating marasmus from kwashiorkor; fatty liver also develops in • kwashiorkor • Growth failure is more severe in marasmus. 13.6.3 Vitamin deficiencies Multiple vitamin deficiencies frequently accompany PEM. Isolated or grouped vitamin deficiencies (for example, of fat-soluble (Table 13.9) or water-soluble (Table 13.10) vitamins) can also occur in specific circumstances. 13.7 METABOLIC ACID–BASE DISTURBANCES (NON-RENAL) The kidneys and the lungs are intimately involved in the regulation of hydrogen ion concentration. Metabolic acid–base disturbances arise from abnormalities in the regulation of bicarbonate and other buffers in the blood. Acidosis results from an increase in H+ concentration and alkalosis from a fall in H+: The pH is the negative logarithm of H+ – a small change in pH represents a large change in H+ concentration; this is often poorly appreciated in clinical practice. 13.7.1 Metabolic acidosis The metabolic acidoses are conveniently divided on the basis of the anion gap. Anion gap = Na+K+(Cl– + HCO3–) The normal anion gap is 10–18 mmol/L and represents the excess of negative charge (unmeasured anions) present on albumin, phosphate, sulphate and other organic acids, eg lactic acid Relationship of metabolic acid to anion gap • • Normal anion gap • Diarrhoea (or other GI loss) • Renal tubular acidosis • Hypoaldosteronism • Treatment of ketoacidosis Increased anion gap • Lactic acidosis • Ketoacidosis • Acute kidney injury and advanced CKD • Hepatic failure • Toluene ingestion • Intoxications, eg methanol, aspirin, ethylene glycol Table 13.9 Deficiencies of fat-soluble vitamins Causes of deficiency syndromes Roles of vitamin Vitamin A Severe PEMa Night blindness Component of visual pigment c Maintenance of specialised Xerophthalmia Follicular epithelia d hyperkeratosis b Bitot’s spots Keratomalacia Vitamin D Veganse Elderly with poor diet CKD Absorption of calcium and phosphate Bone mineralisation Vitamin Vitamin E Severe (near-total) fat Antioxidant malabsorptionf Abetalipoproteinaemia Scavenger of free radicals Cofactor in carboxylation of Deficiency Rickets Osteomalacia Spinocerebellar degeneration Vitamin K Oral antibioticsg coagulation cascade factors Bleeding tendency Biliary obstruction PEM, protein–energy malnutrition. aAlthough vitamin A is fat-soluble and deficiency can occur in any chronic malabsorptive state, this is rare unless there is severe protein– energy malnutrition. bConjunctival foamy patches are an early sign of vitamin A deficiency. cXerophthalmia – dryness of the cornea. dKeratomalacia – corneal ulceration and dissolution. eVitamin D is produced in the skin by photoactivation of 7-dehydrocholesterol. If sun exposure is sufficient, dietary vitamin D is not 3 essential. fVitamin E deficiency is rare. It can complicate biliary atresia. In abetalipoproteinaemia (see earlier section), chylomicrons cannot be formed. gAntibacterial drugs interfere with the bacterial synthesis of vitamin K. Table 13.10 Deficiencies of water-soluble vitamins Vitamin Causes of deficiency Roles of vitamin Vitamin B1 (thiamine)a Alcoholism Nerve conduction Dietary Bariatric surgery Coenzyme in decarboxylation Deficiency syndromes Dry beri-beri – symmetrical Polyneuropathy Wernicke–Korsakoff syndrome Wet beri-berib – peripheral vasodilatation, heart failure Angular stomatitis Glossitis Corneal vascularisation Vitamin B2 (riboflavin) Severe PEMc Enzyme cofactor Niacin (nicotinic acid) Carcinoid syndromed Alcoholism Low-protein diets Isoniazide Pellagra – dementia, Incorporated into NAD dermatitis and and NADP diarrhoea (the three Ds) Vitamin B6 (pyridoxine)f Isoniazid Hydralazine Vitamin B12 (cyanocobalamin) Pernicious anaemia Coenzyme for DNA Post-gastrectomy Vegan synthesis; coenzyme in diet Terminal ileal myelin metabolism Enzyme cofactor Peripheral neuropathy Dermatitis Glossitis Pernicious anaemia Subacute combined degeneration of the disease Blind loops Vitamin Cg Dietary spinal cord Redox reactions Collagen formation Scurvy – bleeding, joint swelling, hyperkeratotic hair follicles, gingivitis aThiamine deficiency is confirmed by reduced red-cell transketolase activity. bIn people with alcohol problems, wet beri-beri must be distinguished from alcoholic cardiomyopathy. cRiboflavin deficiency usually occurs with multiple deficiencies. dIn the carcinoid syndrome (and to a lesser extent in phaeochromocytoma) tryptophan metabolism is diverted from nicotinamide to form amines. eIsoniazid can lead to deficiency of pyridoxine, which is needed for the synthesis of nicotinamide from tryptophan. fDietary deficiency of pyridoxine is extremely rare. gDeficiency of vitamin C is confirmed by low white-cell (buffy coat) ascorbic acid levels. Specific metabolic acidoses Metabolic acidosis with diarrhoea The GI secretions (below the stomach) are relatively alkaline and have a high potassium concentration. There is usually hypokalaemia, low urinary potassium loss (<25 mmol/L) and low urine pH (<5.5). Causes include: • • • • Villous adenoma Enteric fistula Obstruction Laxative abuse. Renal tubular acidosis RTA describes diseases/conditions in which there is a net urinary reduction in acid excretion, resulting in metabolic acidosis. This can be due to reduced acid excretion (reduced H+ secretion in type 1), increased bicarbonate excretion (as a result of loss of bicarbonate reabsorption in type 2 RTA) or reduced ammonia production (type 4 RTA). In type 4 RTA the kidney is either resistant to aldosterone or plasma aldosterone levels are low. This results in hyperkalaemia, reduced ammonia production and acidosis. It is the most common RTA and occurs in patients with tubulointerstitial disease such as diabetes. The RTAs are covered in more detail in Chapter 15, Nephrology. Metabolic acidosis with ureteric diversion and ileal loop diversion This results in hyperchloraemic acidosis in 80% of ureterosigmoid diversions. The mechanism is due to urinary chloride exchange for plasma bicarbonate, which is then lost in the urine. Urinary ammonia is also absorbed across the sigmoid epithelium. Ileal loop diversions also result in significant hyperchloraemic acidosis but less so than ureterosigmoid diversions. Metabolic acidosis accompanying poisoning Metabolic acidosis often accompanies poisoning (eg toluene, ethylene glycol, salicylates, paracetamol). (See also Chapter 2, Clinical pharmacology, toxicology and poisoning.) 13.7.2 Metabolic alkalosis Metabolic alkalosis is less common than metabolic acidosis because metabolic processes produce acids as by-products, and also because renal excretion of excess bicarbonate is very efficient. Many causes of metabolic alkalosis are associated with hypokalaemia. Metabolic alkaloses • • • • • Gastrointestinal hydrogen ion loss • Vomiting/pyloric stenosis • Nasogastric suction • Antacids (in CKD) Intracellular shift of hydrogen ion • Hypokalaemia Alkali administration Renal hydrogen ion loss • Mineralocorticoid excess, eg Cushing syndrome • Loop or thiazide diuretics • Post-hypercapnic alkalosis • Hypercalcaemia and the milk-alkali syndrome Contractional alkalosis • Volume depletion Specific metabolic alkaloses Gastric loss of hydrogen ions In protracted vomiting (eg pyloric stenosis) or nasogastric suction there can be complete loss of up to 3 L of gastric secretions per day. The gastric secretions contain: • Hydrogen ions: 100 mmol/L • Potassium: 15 mmol/L • Chloride: 140 mmol/L. Alkalosis will result but, paradoxically, acid urine is produced due to renal tubular sodium bicarbonate reabsorption to maintain plasma volume. Patients respond to volume expansion with physiological saline and correction of hypokalaemia. Milk-alkali syndrome This is defined as the triad of hypercalcaemia, metabolic alkalosis and ingestion of large amounts of calcium with absorbable alkali (traditionally for peptic ulcer pain). The hypercalcaemia increases renal bicarbonate reabsorption, exacerbating the alkalosis. Clinical presentation is with symptoms of hypercalcaemia or metastatic calcification. Post-hypercapnic alkalosis Chronic respiratory acidosis leads to a compensatory increase in urinary hydrogen ion secretion, resulting in a rise in plasma bicarbonate concentration. Rapid lowering of a raised PCO2 (usually by mechanical ventilation) is not immediately accompanied by a fall in plasma bicarbonate. There is often an accompanying chloride loss that must be replaced before bicarbonate can fall to normal. 13.8 HYPOTHERMIA Hypothermia is defined as a fall in core temperature to <35°C. It is frequently fatal if the core temperature falls to <32°C. Hypothermia must be classified by the duration of hypothermia: • Acute (immersion) hypothermia: rapid loss of heat, eg fall into cold water • Subacute (exhaustion) hypothermia: patients are unable to generate heat due to exhaustion Chronic hypothermia: a gradual loss of heat often seen in elderly patients with inadequate • heating and homeless people. Causes of hypothermia • • • Exposure to low external temperatures • Elderly and very young people with inadequate heating • Immersion in cold water • Mountaineers Medical conditions • Hypothyroidism • Hypoglycaemia • CNS disorders, eg stroke, hypopituitarism • Post-cardiac arrest and unconscious patients Drugs • General anaesthetics resulting in perioperative hypothermia • Alcohol • Sedative drugs, eg benzodiazepines and narcotics Mild hypothermia (32–35°C) causes shivering and intense feeling of cold, altered judgement and ataxia. Moderate hypothermia (28–32°C) can cause confusion and drowsiness; patients are often unconscious and lose the ability to shiver. The risk of arrhythmias increases. Severe hypothermia (<28°C) increases the risk of asystole, coma, apnoea, fixed pupils, pulmonary oedema and death. Clinical features of hypothermia include bradycardia, hypoventilation, muscle stiffness, cold • diuresis, hypotension and loss of reflexes. The pupils can be fixed and dilated in recoverable hypothermia Metabolic acidosis due to lactate accumulation is common; pancreatitis can complicate • hypothermia Electrocardiograph changes include J waves, prolonged P–R interval, prolonged QT and QRS • complexes. Death results from ventricular arrhythmias or asystole. In certain medical situations therapeutic hypothermia (cooling to 32–34°C) can be induced (eg after cardiac arrest, complex cardiac surgery). This reduces tissue oxygen requirements and can improve patient outcomes. 13.8.1 Treatment of hypothermia Hypothermia >30°C: surface rewarming is usually adequate with removal of wet clothes, and provision of warm blankets and heaters. Hypothermia <30°C: active internal warming until core temperature is at least 32°C using warm intravenous fluids and warm humidified oxygen. If necessary, peritoneal lavage, pleural lavage and haemodialysis can also be helpful. Cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO) can be used in patients who are in ventricular fibrillation or have profound hypothermia and are deteriorating. Cardiac arrest in the hypothermic patient Severe hypothermia can mimic death. Consequently cardiopulmonary resuscitation should be continued in hypothermic patients until the patient has been rewarmed or until all attempts have failed to improve core temperature. The hypothermic heart has reduced responsiveness to cardiac drugs, pacemakers and defibrillation. Cardioactive drugs can also accumulate as drug metabolism is decreased. Therefore, intravenous drugs are often withheld until core temperature is >30°C. Hypothermia protects the brain during cardiac arrest, so patients can have a full neurological recovery despite prolonged cardiac arrest. aUK NICE guidelines do not recommend cinacalcet for the routine treatment of secondary hyperparathyroidism because it has not been shown to be cost-effective. It can be used in patients who have failed to respond to other treatments or in patients with tertiary hyperparathyroidism who are unsuitable for parathyroidectomy. Chapter 14 Molecular Medicine CONTENTS 14.1 Molecular diagnostics 14.1.1 Genomes, transcriptomes, proteomes and metabolomes 14.1.2 The polymerase chain reaction 14.1.3 Reverse transcription PCR 14.1.4 Monoclonal antibodies 14.1.5 Antibody-based assays 14.2 Cell signalling 14.2.1 Types of receptor 14.2.2 Protein kinases and phosphatases 14.2.3 Nuclear hormones 14.2.4 Transcription factors and the regulation of gene expression 14.3 The molecular pathogenesis of cancer 14.3.1 Somatic evolution of cancer 14.3.2 Oncogenes 14.3.3 Tumour suppressor genes 14.4 Apoptosis and disease 14.5 Molecular regulation of vascular tone 14.5.1 Nitric oxide 14.5.2 Endothelin-1 14.6 Molecular mediators of inflammation, damage and repair 14.6.1 Interleukin-1 14.6.2 Tumour necrosis factor 14.6.3 Transforming growth factor β 14.6.4 Heat shock proteins 14.6.5 Free radicals and human disease 14.7 Transmissible spongiform encephalopathies 14.8 Adhesion molecules 14.9 Stem cells 14.10 The molecular basis of some important diseases 14.10.1 Amyloidosis 14.10.2 α1-Antitrypsin deficiency 14.10.3 Alzheimer’s disease 14.10.4 Trinucleotide repeat disorders 14.10.5 Mitochondrial disorders 14.10.6 Myasthenia gravis 14.10.7 Duchenne muscular dystrophy 14.10.8 Sickle cell disease 14.11 Glossary of terms in molecular medicine Molecular Medicine 14.1 MOLECULAR DIAGNOSTICS The diagnostic process in medicine has entered a new and important historical phase. Increasingly, diagnostic entities are being reclassified according to the molecules that are central to the disease process and also according to changes in the expression of genes that code for these molecules. With the advent of the complete human gene sequence we now have the tools for a complete understanding of how cells develop and how they function in health and disease. 14.1.1 Genomes, transcriptomes, proteomes and metabolomes The genome of an organism is its complete complement of coding genes. Comparison of the organisms in Table 14.1 reveals that the level of complexity of an organism is not explained by the number of genes predicted to code for protein. Fruit flies (Drosophila melanogaster, a favourite organism for geneticists) have more complex behaviours than nematode worms (Caenorhabditis elegans) but fewer genes. One reason for this is that flies process genes in a more complex way. Humans and mice have the same number of predicted genes and 98% of these are orthologues (have a common ancestral gene and code for equivalent proteins). Biological complexity is explained by: • • • • The transcriptome: this is the name given to the total complement of expressed mRNA sequences in an organism. In lower organisms, this will be the same as the number of genes. In mammals, genes are transcribed in a more complex way, with transcription being initiated from different exons in different tissues and alternative splicing (post-transcriptional processing). The temporal (when in development) and spatial (in which cells) expression of genes allows significant diversity which is not evident just from looking at gene number. It is likely therefore that the transcriptomes of mice and humans contain significant differences Processed mRNA is translated into protein. Similarly, differences in mRNA transport, localisation and stability mean that the proteome cannot be inferred directly from the transcriptome Post-translational processing: proteins can be modified by glycosylation, sialylation, etc. Protein stability and turnover may be very different in different cell types and between similar cells in different organisms Finally, the progressive diversity of the proteome with evolution leads to an exponential amplification of combinatorial possibilities between proteins. Therefore, although the human genome may have 30 000 information units (genes), the final number of information units needed to explain human biological complex is theoretically several orders of magnitude greater. Table 14.1 The genomes of various organisms Organism Number of proteins Approx. genome size Human Mouse Fruit fly Nematode Fission yeast Bacterium 30 000 30 000 13 500 19 000 6000 2000–6000 3 × 109 (3 Gb) 3 Gb 40 × 106 (40 Mb) 96 Mb 12 Mb 2–6 Mb Introns Splicing Yes Yes Yes Very few Rare Absent Highly complex Complex Yes Very little Absent Absent The Human Genome Project The Human Genome Project (HGP) was possibly the greatest scientific undertaking in recent history. The project began in 1990 and sequencing was completed in 2003. Analysis of the vast amounts of data generated by the project is still ongoing, but medical science has already profited from the results. As a direct consequence of the HGP, genetic tests are now available that show predisposition to a range of diseases, including breast cancer, cystic fibrosis and liver diseases. The main goals of the HGP were as follows: • • • • • • Identify all the approximately 20 000–25 000 genes in human DNA Determine the sequences of the 3 billion chemical base pairs that make up human DNA Store this information in databases Improve tools for data analysis Transfer related technologies to the private sector Address the ethical, legal and social issues (ELSIs) that may arise from the project. Ten years after the completion of the HGP, there is still no definitive number of genes in the human genome, and is a topic of much conjecture. The most recent study in 2012 found 20 687 proteincoding genes. The HGP created the field of genomics, that of understanding genetic material on a large scale. The field of medicine is profiting from the HGP as we learn more about the genetic contribution to disease. Epigenetics Epigenetics (meaning above genetics) is the study of modifications to DNA that do not affect the sequence, but can alter levels of gene activation. Epigenetic modifications alter the physical structure of DNA, which in turn alters the ability for transcription factors and the transcriptional apparatus to access particular genes. The epigenetic status of any particular gene can vary across cell types, whilst the DNA sequence does not. This confers a mechanism by which we can get different cell-specific gene activation states. Chromatin structure and epigenetics A good understanding of chromatin structure is important in understanding epigenetics. The DNA contained in a chromosome, if it were not compacted in some way, would take up too great a volume to be contained in a cell. The DNA is therefore condensed by tightly packing it into a smaller structure, a chromosome. A chromosome is actually a complex of DNA, protein and RNA. The smallest unit in a chromosome is a nucleosome. A nucleosome consists of 147 base pairs (bp) of double-stranded DNA wrapped around an octamer of proteins called histones. This octamer is made up of two copies of a heterotetramer that consists of histones H2A, H2B, H3 and H4 (Figure 14.1). The DNA wraps around this ‘core octamer’ of histones twice and then binds to a single H1 histone. The appearance of DNA wrapped around an octamer of histones has led to it being referred to as ‘beads on a string’. The H1 histone does not form part of the ‘bead’ but binds to the top of the structure, stabilising the ‘linker DNA’ region (a 20-to 28-bp length of DNA in-between nucleosomes) and keeping in place the DNA that is wrapped around the core octamer of histones (Figure 14.2). The nucleosome ‘beads on a string’ then tightly pack to form chromatin, and the chromatin coils and packs into the chromosome (Figure 14.3). In mammalian cells most chromatin is found in the form of heterochromatin. Heterochromatin is a highly condensed, transcriptionally silent form of chromatin. In regions of DNA that contain transcriptionally active genes, the chromatin is termed ‘euchromatin’. Euchromatin is less condensed than heterochromatin and allows transcription factors and the transcription apparatus access to the DNA. Figure 14.1 Chromatin consists of DNA spooled around a complex of histone proteins Figure 14.2 The H1 histone binds outside the nucleosome and stabilises the linker DNA Figure 14.3 From DNA to chromosome Epigenetic markers Epigenetic markers are chemical modifications to histones and DNA that can affect chromatin structure, making it either easier or harder for transcription factors and the transcriptional apparatus to access regions of DNA. They do this by altering the electrostatic nature of the chromatin or by altering the affinity of chromatin-binding proteins. DNA methylation DNA methylation is vital for normal development and is associated with a number of key cellular processes including cell differentiation, carcinogenesis, genomic imprinting, X-chromosome inactivation and suppression of repetitive elements. DNA methylation is the addition of a methyl group to the 5′ position of the cytosine pyrimidine ring by a methyltransferase enzyme. DNA methylation is not irreversible. As there is a family of DNA methylase enzymes, so there are mechanisms of removing methylated cytosines (not thought to be through direct removal of the methyl group, but by replacement of the methylated cytosine with an unmethylated one). The vast majority of cytosine methylation occurs in cytosines immediately followed by a guanine base (5′-CG-3′). This sequence is termed a CpG site. In mammalian cells between 60% and 90% of all CpGs are methylated. The variably methylated CpG sites are the important ones and these tend to be found in ‘CpG islands’ located in the 5′-regulatory regions of genes. DNA methylation leads to a decrease in the transcriptional activity of genes and may lead to ‘transcriptional silencing’. DNA methylation can affect the transcription of genes in two ways: The methyl groups added during DNA methylation may cause steric hindrances and prevent the binding of transcription factors More importantly, methylated CpG sites attract and bind a series of proteins called methyl-CpG2. binding domain proteins (MDBs). 1. MDB proteins, once bound, can further recruit other proteins capable of remodelling chromatin, such as histone deacetylases. These proteins convert transcriptionally active euchromatin into transcriptionally silent heterochromatin. In medicine the loss of MDB activity can be crucial. Loss of methyl-CpG-binding protein 2 (MeCP2) has been implicated in Rett syndrome (a neurodevelopmental disorder) and loss of methyl-CpG-binding domain protein 2 (MDB2) mediates the transcriptional silencing of hypermethylated genes in cancer. DNA methylation in cancer Abnormal DNA methylation has been associated with a large number of human cancers and is brought about by both hypermethylation and hypomethylation. Incidences of hyperermethylation in cancer far outnumber those of hypomethylation. The way in which hypermethylation brings about cancer is through the methylation of CpG sites in the 5′-promoter regions of tumour-suppressor genes. This hypermethylation leads to repression of transcription and gene silencing. Genome hypomethylation can result in the activation of germline-specific genes that are normally repressed, primarily, by DNA methylation. This group of genes has been termed ‘cancer-germline genes’. Table 14.2 lists the genes commonly methylated in human cancer. Histone acetylation The association of histones with DNA is vital for the organisation of the billions of base pairs that make up the human genome. The organisation of DNA into chromatin has implications on all DNAdependent events, such as transcription, recombination, replication and repair. The chromatin in a chromosome is not a static structure but rather a dynamic molecule in which changes in the level of organisation can occur in response to the myriad of different signalling pathways found in a cell. There are several mechanisms by which the organisation of chromatin may be dynamically changed. Transcriptional silencing through DNA methylation is not a dynamic process, although methylation can be reversed it cannot be done in a timely manner that would allow for rapid response to acute signalling pathways. The most notable mechanism of dynamic chromatin regulation is brought about through post-translational changes to histones. The most widely understood histone modification is acetylation. Histones are proteins that are rich in positively charged lysine residues. These positive charges form a strong association with the negatively charged DNA. By the addition of an acetyl group to the lysine rich amino-terminal tails of histones by dedicated histone acetlytransferases (HATs), these positive charges are removed and the histone’s association with DNA is weakened. With a decreased affinity for DNA there is a ‘relaxation’ in the chromatin structure which can increase the access of transcription factors to the upstream regulatory region of genes. Table 14.2 Genes commonly methylated in human cancer and their role in tumour development Gene Role in tumour development Site of tumour APC Deranged regulation of cell proliferation, cell migration, cell adhesion, cytoskeletal reorganisation and chromosomal stability BRCA1 Implicated in DNA repair and transcription activation Breast Lung Oesophageal Breast Ovarian GIT Head and neck NHL Lung CDKN2A/p16 Cyclin-dependent kinase inhibitor DAPK1 E-cadherin ER GSTP1 hMLH1 MGMT p15 RASSF1A Calcium/calmodulin-dependent enzyme that phosphorylates serine/threonine residues on proteins; suppression of Lung apoptosis Breast Increasing proliferation, invasion and/or metastasis Thyroid Gastric Breast Hormone resistance Prostate Prostate Loss of detoxification of active metabolites of several Breast carcinogens Renal Colon Gastric Defective DNA mismatch repair and gene mutations Endometrium Ovarian p53-related gene involved in DNA repair and drug Lung resistance Brain Leukaemia Lymphoma Unrestrained entry of cells into activation and proliferation Squamous cell carcinoma, Lung Lung Breast Loss of negative regulator control of cell proliferation Ovarian through inhibition of G1/S-phase progression Kidney Rb VHL Failure to repress the transcription of cellular genes required for DNA replication and cell division Altered RNA stability through and erroneous degradation of RNA-bound proteins Nasopharyngeal Retinoblastoma Oligodendroglioma Renal cell cancer GIT, gastrointestinal tract; NHL, non-Hodgkin’s lymphoma. The acetylation of histones, and hence all effects on chromatin structure, can be reversed by the removal of the acetyl groups by dedicated histone deacetylases (HDACs). The interplay of HATs and HDACs results in dynamic changes in chromatin structure which in turn leads to changes in the activation state of genes. Disregulation of HATs and HDACs has been linked to the progression of cancers as well as various syndromes such as Rubinstein–Tabi and fragile X syndromes. Histone deacetylase inhibitors (HDIs) are an established group of drugs used as mood stabilisers and antiepileptics. They are showing increasing promise in the treatment of cancer where they have been shown to induce differentiation, cell-cycle arrest and apoptosis, and to inhibit migration, invasion and angiogenesis. Inheritance of epigenetic markers It used to be thought that all epigenetic marks were removed in the genetic material included in gamete cells. It was thought that epigenetic tags were not inherited and that an embryo had a clean epigenome that was rebuilt from scratch. We now know this not to be the case. Most, but not all, epigenetic information is removed, but some tags remain in place and are passed from generation to generation in ‘epigenetic inheritance’. Epigenetic inheritance has profound implications. It means that as well as information from our genetic code being passed on, so can information from our experiences in life, in the form of epigenetic marks. Epigenetic inheritance has been shown through the altered traits of offspring in response to their parents’ experiences. Periods of famine have resulted in health effects in the children and grandchildren of individuals that had severely restricted diets. Their genetic code had not changed, but epigenetic tags caused by the restricted diet have been inherited and have then affected gene expression profiles of subsequent generations. Normally epigenetic marks are erased in sperm and egg precursor cells (primordial gene cells, PGC). Methylation marks are converted to hydroxymethylation which is progressively diluted out as cells divide. However, some rare methylation can ‘escape’ the reprogramming process and therefore may be inherited by subsequent progeny. Fluorescent in situ hybridisation Fluorescent in situ hybridisation (FISH) is a technique that, using fluorescently labelled DNA probes (often derived from fragments of DNA that were isolated during the HGP), can detect and confirm gene and chromosome abnormalities beyond the resolution of routine cytogenetics. Sample DNA is first denatured, converting double-stranded to single-stranded DNA. The fluorescently labelled probe (complementary to the DNA sequence of interest) is then added to the single-stranded DNA. If the DNA sequence of interest is present in the sample, the probe hybridises with the complementary bases as the DNA re-forms back into a double helix. The probe signal can then be detected through a fluorescence microscope and the sample DNA scored for the presence or absence of the signal. FISH can be performed using two sample types: metaphase chromosomes and interphase nuclei. Metaphase FISH FISH can be performed on metaphase chromosomes to detect specific microdeletions undetectable by routine cytogenetics, or to identify chromosome translocations or extra material of unknown origin. Microdeletion syndromes currently detectable using FISH • Cri-du-chat syndrome A syndrome that results from the deletion of part of the short arm of chromosome 5. The main clinical feature is the presence of a high-pitched ‘cat-like’ cry present in the newborn that may disappear with age. Other features include a round, full face, widely spread eyes • (hypertelorism), an extra fold of skin at the inner corners of the eyes (epicanthal folds), a flattened and widened nasal bridge and ears that are positioned low on the head, severe cognitive, speech and motor delays, and feeding problems from birth which may lead to poor growth • Miller–Dieker syndrome A congenital malformation syndrome that results from the deletion of several adjacent genes in the short arm of chromosome 17 (17p). Clinical features include lissencephaly and a characteristic facial appearance (prominent forehead with bitemporal hollowing, short nose • with upturned nares, thickened upper lip with a thin vermilion upper border, widely spaced eyes, low ears, and small jaw). The syndrome may result in mental retardation, epilepsy, preand postnatal growth retardation, and reduced lifespan. There may also be multiple abnormalities of the brain, kidneys, heart, and gastrointestinal tract • Smith–Magenis syndrome Results from a microdeletion in the short arm of chromosome 17 [del(17)(p11.2 p11.2)]. As well as characteristic facial abnormalities (short flat head, prominent forehead, broad square • face, upslanting eyeslits, deep-set eyes, underdeveloped midface, broad nasal bridge, short nose and tented upper lip), the syndrome may also cause mild-to-moderate mental retardation • Steroid sulphatase deficiency Also known as X-linked ichthyosis, it is a genetic disorder of the skin that occurs only in males. The condition develops in infancy and manifests as tan or grey scales on the skin that • are a result of a deficiency in the enzyme steroid sulphatase due to genetic mutations of the gene DiGeorge syndrome (also known as velocardiofacial/CATCH-22/Shprintzen syndrome) (see • Chapter 7, Section 7.1.3 and Chapter 10, section 10.9.4) • Kallman syndrome (see Chapter 4, section 4.8.3) • Williams syndrome (see Chapter 1, section 1.3.5 and Chapter 7, section 7.1.3) • Wolf–Hirschhorn syndrome Results from a partial deletion of the short arm of chromosome 4. Many parts of the body are affected by this syndrome as the deletion affects fetal growth and development. Common • features include profound learning disability, microcephaly, seizures, low muscle tone and poor muscle development, heart defects, and cleft lip and/or palate Interphase FISH FISH can be used in interphase cells to determine the chromosome number of one or more chromosomes as well as to detect some specific chromosome rearrangements characteristic of certain cancers. The advantage of interphase FISH is that it can be performed very rapidly as cell growth is not required. An example of interphase FISH is the aneuploid screen test performed on amniotic fluid cells to determine the presence of the common trisomies. Sample nuclei are denatured and incubated with probes for chromosomes 13, 18, 21, X and Y. Transcriptomics The gene expression profile (transcriptome) of a particular tissue is the key to understanding the cell phenotype in health and disease. An average cell expresses about 16 000 genes throughout its lifetime, but clearly the range of genes expressed in the lifetime of an individual cell will vary during development, maintenance and ultimately cell death. Inevitably the genes expressed by a neuron in the cerebellum will be very different from those expressed by a lymphocyte, though housekeeping genes are common to many cells and encode constitutive cellular processes. The transcriptome of a cell can be captured using a technique known as microarray analysis. This depends on the same hybridisation reaction as other nucleic acid techniques but represents dramatic scaling up of the procedure, such that many thousands of hybridisation reactions occur on a single medium and changes in transcription in many genes can be assessed simultaneously. RNA is prepared from the tissue of interest (eg a tumour biopsy specimen) and from a control sample (eg normal tissue from the same organ from which the biopsy was obtained). The RNA is hybridised to a ‘DNA chip’. This consists of a silicon slide 1–2 cm in size onto which have been spotted oligonucleotides, 20–30 bp long. Each oligonucleotide represents a particular gene. The RNAs from the abnormal and control tissues are labelled with different colour fluorescent dyes (eg red and green) and the level of expression of many thousands of genes can then be analysed by computer software, which compares the differences in intensity generated by the hybridisation reaction. The power of this technology is such that it is not necessary to know anything about the function of the particular gene spotted onto the chip As the sequence of every gene is now known, DNA chips with a representative coverage of the • whole human genome can be produced commercially It is also possible to produce tissue-specific chips (eg human CNS) or chips with a limited • number of genes of interest for use in diagnostics, when a specific question is being asked DNA microarrays can in principle identify a whole array of downstream genetic consequences of • a particular gene mutation and provide a molecular profile of a disease state that can act as a • marker of therapeutic effect. Practical applications • • • • Rapid sequencing for many genetic mutations can be performed simultaneously in a highthroughput approach, eg specific oligonucleotides that recognise all of the mutations responsible for a particular disease can be spotted onto a chip and DNA from an affected individual analysed Tumours or other abnormal tissue can undergo molecular profiling in order to identify patterns of gene expression, eg it is now possible in clinical practice to use microarrays to analyse the expression of panels of key genes that determine the clinical response to chemotherapeutic agents in lymphoma. Also, tissue or fluid from infections can be analysed for the expression of genes conferring antibiotic resistance before organisms have even been cultured Though still a research tool, it is likely that microarrays will be routinely used in the near future in genotyping large numbers of genes simultaneously to look at specific disease risk (eg cardiovascular) associated with single nucleotide polymorphisms (SNPs) or other genetic variants Individual responses to common drug treatments (eg antihypertensive agents) are likely to have a basis in genetic variation. The application of knowledge acquired through genetic profiling such as with microarrays is known as pharmacogenomics. Proteomics As discussed above, the total protein content of a cell or tissue may be a more meaningful target for analysis in certain situations than either the genome or transcriptome. Protein from whole tissue or from subcellular fractions (eg membrane, nuclear, mitochondrial) can be separated by physical methods, such as on a two-dimensional gel, in which proteins are resolved by charge and mass to produce individual spots on a polyacrylamide gel which can then be silver stained. Individual spots of interest can be removed and eluted from the gel. The protein within can then be identified using tandem mass spectrometry which can sequence short peptides. A known protein can then be identified by reference to protein sequence databases. Where the oligopeptide does not produce a match, a search can be made of the human genome sequence databases – computer programs have been used to predict genes and therefore protein sequences from the primary data (an example of what is known as bioinformatics). Currently, proteomics is largely a research tool, but with time and improved technology it will inevitably be used in clinical practice. Potential applications The identification of all of the proteins expressed in a particular cell, groups of cells or whole tissues throughout the whole development of an organism from conception to death. Ultimately a • complete description of the ontogeny of the cell will be possible allowing virtual modelling and computer-based drug design Comparisons can be made between healthy and diseased tissue in the same way as for mRNA with microarrays. However, the advantage with proteomics is that it may be possible to detect • differences at the protein level that are not reflected at the transcriptional level due to changes in turnover or post-translational processing. As with RNA techniques, protein from different sources can be differentially labelled with fluorescent dyes to aid the detection of differences Protein chips contain antibodies spotted onto silicon-based media similar to microarrays. • Several hundred targeted proteins can be analysed in this way. Metabolomics Metabolomics is the study of the specific and unique metabolite profile left behind by cellular processes. In different disease states it is thought that this profiles small metabolite changes. If characteristic profiles for specific diseases can be determined, it may be used as a diagnostic tool. The metabolome is the complete set of smallmolecule metabolites found in an organism. Similar to the transcriptome and proteome, the metabolome is constantly changing. At present the Human Metabolome Project (http://metabolomics.ca) has identified and quantified over 300 metabolites in cerebrospinal fluid, over 1000 metabolites in serum, over 400 metabolites in urine and approximately 300 metabolites in other tissues and biofluids, but the major limiting factor in the application of this technology is the incomplete characterisation of the human metabolome. With many of the molecules being small and difficult to extract, further work is required so that we can use the ‘whole’ metabolome in disease diagnosis. The metabolome of an organism is related to both its genotype and its physiology, and can also be affected by its environment (what it eats and breathes). This complex interaction therefore allows us to look at genotype–phenotype as well as phenotype–environment relationships. Metabolomics technology is increasingly used in a variety of health applications, including pharmacology, preclinical drug trials, toxicology, transplant monitoring, newborn screening and clinical chemistry. There are four key steps: 1. Efficient and unbiased extraction of the metabolites from biological samples Separation of the analytes (typically by chromatography, either gas or high-performance liquid 2. chromatography) Detection of the metabolites after separation (usually by either mass spectrometry [MS] or 3. nuclear magnetic resonance [NMR]) 4. Identification and quantification of detected metabolites. Physicians are now coming to understand that metabolic profiling can be used in the diagnosis, prediction, prevention and monitoring of many genetic, infectious and environmental diseases. In practice, complex computer software looks for patterns and changes in the metabolic profile from samples taken from patients with a particular disease compared with healthy controls. Having been ‘taught’ that a particular pattern is characteristic of a disease, samples from patients with unknown disease status can then be screened comparatively. 14.1.2 The polymerase chain reaction The polymerase chain reaction (PCR) is an amplification reaction in which a small amount of target DNA (the template) is amplified to produce enough to perform analysis. This might be the detection of a particular DNA sequence, such as that belonging to a pathogenic microorganism or an oncogene, or the detection of differences in genes, such as mutations causing inherited disease. Therefore, the template DNA might consist of total human genomic DNA derived from peripheral blood lymphocytes, amniocentesis or chorionic villous sampling; alternatively, it might consist of a tumour biopsy or a biological fluid from a patient with an infection. Two unique oligonucleotide sequences, known as primers, are mixed with a DNA template and a thermostable DNA polymerase (Taq polymerase, derived from an organism that inhabits thermal • springs). Sometimes more than two primers can be used if more than one gene is to be amplified (multiplex PCR) or the region of DNA to be amplified needs special definition (‘nested’ PCR), eg if it is similar to other sequences in the genome which may give spurious reaction products In the initial stage of the reaction, the DNA template is heated (typically for about 30 seconds) to • make it single-stranded and then as the reaction cools, the primers will anneal to the template if the appropriate sequence is present Then the reaction is heated to 72°C (for about a minute) and the DNA polymerase synthesises • new DNA between the two primer sequences. During 30 or so cycles (each typically lasting a few minutes) the target sequence will have been amplified exponentially. The crucial feature of PCR is that to detect a given sequence of DNA, it needs to be present only in one copy (ie one molecule of DNA); this makes it extremely powerful. Clinical applications of PCR • Mutation detection Detection of viral and bacterial sequences in tissue (herpes simplex virus in CSF, hepatitis C, • HIV in peripheral blood, meningococcal strains) • Single-cell PCR of in vitro fertilised embryo to diagnose genetic disease before implantation In the example in Figure 14.4, some CSF from a patient suspected of having herpes simplex encephalitis is used in a PCR reaction in an effort to detect the presence of the virus directly. Small amounts of target DNA are amplified with a thermostable DNA polymerase. 14.1.3 Reverse transcription PCR Conventional PCR looks at genomic DNA. Every cell in our body contains our total genome in two copies. However, the phenotype of a cell (what makes a hepatocyte different from a Purkinje cell) depends on which genes are being expressed at any one time. To look at the expression of genes we must therefore analyse only those genes that are being transcribed into mRNA. RNA is too unstable to be used in PCR so it must first be converted to complementary DNA (cDNA) using reverse transcriptase, a retroviral enzyme that makes a precise copy of the mRNA PCR is then performed in the normal way but, as the template reflects the mRNA of the starting • material, this technique can look at gene expression in individual tissues. • Figure 14.4 The polymerase chain reaction (PCR) Clinical applications of reverse transcription PCR (rtPCR) Detection of the expression of particular genes in tumour tissue carries important prognostic information Basic scientific research into normal function of disease genes by understanding their spatial and • temporal expression • 14.1.4 Monoclonal antibodies The detection of specific proteins in molecular diagnosis relies on the fact that the antibody used has a high specificity for the target protein. An immune response to an antigen consists of a polyclonal proliferation of cells giving rise to antibodies with a spectrum of specificity for the target. Therefore, useful diagnostic and therapeutic antibodies must be selected from this complex immune response before they can be used. Myeloma is a malignantly transformed B-cell lineage that secretes a specific antibody. This fact is used to produce unlimited amounts of specific antibodies directed towards an antigen of choice. A laboratory animal is injected with the antigen of choice (Figure 14.5); it mounts an immune • response and its spleen, which contains B-cell precursors with a range of specificity for the antigen, is harvested • The spleen cells are fused en masse to a specialised myeloma cell line that no longer produces its own antibody The resulting fused cells, or hybridomas, grow in individual colonies, are immortal and produce • antibodies specified by the lymphocytes of the immunised animal. These cells can be screened to select for the antibody of interest which can then be produced in limitless amounts. Figure 14.5 Monoclonal antibody production Clinical applications of monoclonal antibodies • • • • Diagnosis of cancer and infections Imaging of tumours, radiotherapy As a ‘magic bullet’ to direct drugs to target Transplantation and other immune modulations (eg OKT3) Limitations of monoclonal antibody therapies The specificity of binding of monoclonal antibodies makes them excellent therapies where specific disease-related antigens are present. There are, however, limitations to using murine/rabbit monoclonal antibodies. As the antibody was produced in a foreign species, the human body recognises it as foreign and mounts an immune response against it. A mouse/rabbit IgG antibody is made of two main domains: the variable region, which confers the specificity of binding, and the constant region, an area that is not involved in binding so can remain the same between different IgGs. If the human anti-mouse/rabbit antibodies are raised against the variable region, then any further treatments with that therapy will be rapidly cleared by the immune system before it can reach its therapeutic target. Treatment with other antibody therapies will be unaffected. If the human antimouse/rabbit antibodies are raised against the constant region of the IgG, because these regions are shared in all mouse/rabbit IgGs, not only that drug, but any subsequent IgG therapy, will be rapidly cleared (Figure 14.6). Humanisation of monoclonal antibodies In response to the limitations of use of monoclonal antibodies as a therapy, scientists have tried to decrease the immunogenicity of the murine/rabbit IgGs. Initially this was brought about through the creation of chimeric and humanised antibodies. A chimeric antibody is one that still has the murine/rabbit variable region, but fused to human constant regions. Overall this results in a protein that is made up of 65% human regions. This may trick the human immune system into thinking that the protein is native so as to alleviate an immune response against it. The 35% murine/rabbit regions do still mean that there is a chance that the antibody will be recognised as foreign, however. Figure 14.6 The immunogenicity of monoclonal antibodies A humanised antibody goes one step further and uses only a small portion of the mouse/rabbit variable region, the hypervariable region that is most responsible for antigen binding, and fusing it into human domains. This can result in a protein that is up to 95% human, which results in a much reduced immunogenicity, but as the whole mouse/rabbit variable region is not used there is usually a drop in antibody-binding affinity. Recently scientists have been creating human monoclonal antibodies. These antibodies are still created in a mouse/rabbit using the same method as described, but the mouse/rabbit is transgenic. The mouse/rabbit IgG genes have been replaced with human copies. When the mouse/rabbit is immunised with a new antigen, the IgG produced will use human sequences and will therefore have no immunogenicity when used as a therapy. 14.1.5 Antibody-based assays An assay is defined as a procedure where a property or concentration of an analyte is measured. In medicine the specific binding of labelled antibodies is used to assay for a huge range of analytes that may aid in the diagnosis of disease. Assays are available for numerous serum proteins (growth factors, cytokines, clotting factors, etc) as well as for proteins found on infectious organisms (bacterial and viral). Previous radioactive methodology (radioimmunoassay [RIA] and immunoradiometric assay [IRMA]) is being replaced by enzyme immunoassays, the most common of which is the enzyme-linked immunosorbent assay (ELISA). 1. A plate is coated with capture antibody specific to the analyte of interest (Figure 14.7) Sample is added and incubated for sufficient time to allow any analyte present to bind to the 2. capture antibody; non-specific, unbound proteins are washed off Secondary antibody is added that also recognises the antigen, but which has been raised against a 3. different part of the protein – so both antibodies can bind at the same time. Excess secondary antibody is washed off Enzyme-linked tertiary antibody is added that recognises the secondary antibody; excess tertiary 4. antibody is washed off Substrate is added and is converted by the linked enzyme to a detectable form (fluorescent or 5. colorimetric). The intensity of signal is directly proportional to the amount of analyte present. Concentration is calculated by constructing a standard curve with known amounts of analyte. 14.2 CELL SIGNALLING Central to all cellular processes is the conversion of external signals (first messengers) via intermediates (second messengers) into changes that alter the state of that cell. This often involves adjustment in the expression of genes in the cell nucleus and new protein synthesis. In the following example (Figure 14.8), a photon of light is the external stimulus that produces, via second messengers, a change in the resting state of the rod cell, leading it to transmit a signal to the visual cortex. Figure 14.7 The ELISA (enzyme-linked immunosorbent assay) process Figure 14.8 A typical signalling pathway (the rod receptor). This involves a G-protein-coupled membrane receptor that activates a second messenger pathway 14.2.1 Types of receptor The chief function of the cell membrane is to provide a barrier to ion flux and therefore to maintain the internal milieu of the cell. There are, as described below, certain lipophilic modules that travel freely into the cell. However, most external signals can effect changes only inside the cell by interaction with membrane-bound receptor modules. This biologically ubiquitous system of signal transduction by receptors underlies the action of many hormones, growth factors and drugs. Ligand-gated ion channel For example, acetylcholine receptor (nicotinic): Five non-covalently assembled subunits (α2βγδ) are located at the postsynaptic neuromuscular junction Each subunit is coded for by a different gene, which enables mixing and matching of subunits • between different tissues and in embryological development to generate a repertoire of responses On binding of acetylcholine to the α subunits the whole complex undergoes a conformational • change leading to the passage of sodium ions into the cell and cellular depolarisation. • Other examples include some glutamate receptors (excitatory), γ-aminobutyric acid (GABA) and glycine (inhibitory: the passage of chloride ions into the cell renders it more resistant to depolarisation). Receptors that contain cytoplasmic domains with protein tyrosine kinase activity Insulin binds to its receptor, which then undergoes dimerisation and autophosphorylation at a tyrosine residue • The tyrosine kinase activity intrinsic to the receptor is then activated and the result is the • phosphorylation of cytoplasmic proteins and initiation of an intracellular cascade • This ultimately leads to the action of insulin on glucose uptake, etc. Other examples include platelet-derived growth factor, insulin-like growth factor 1 (IGF-1), macrophage colony-stimulating factor and nerve growth factor. G-protein-coupled receptors Guanine nucleotide-binding proteins are a ubiquitous cellular mechanism for coupling an extracellular signal to a second messenger, such as cAMP (Figure 14.9). G-proteins have three non-covalently associated subunits: α, β, γ. In the inactive state GDP is bound to the α subunit of the G-protein When the receptor is activated by ligand binding, the G-protein is activated by the hydrolysis of • GTP to GDP In this active state the α subunit dissociates from the β and γ subunits. Either of these two • complexes (the GTP-α or the -γ) can then interact with second messengers The α subunit is rapidly inactivated by hydrolysis of GDP to GTP (this is an intrinsic property of • the α subunit, which is therefore known as α-GTPase) and then re-associates with the β and γ subunits, resetting the whole system to the inactive state. • Figure 14.9 G-proteins are activated by ligand binding to a transmembrane receptor G-proteins can be inhibitory (Gi) or stimulatory (Gs) and the overall activity of a second messenger such as adenylyl cyclase is likely to be regulated by the differential activation of these different forms. The muscarinic acetylcholine receptor, the α- and β -adrenergic receptors and the retinal photoreceptor rhodopsin are all G-protein-coupled receptors. These can be linked to a variety of second messenger systems or sometimes directly to ion channels. Diseases associated with G-protein abnormalities Cholera: Vibrio cholerae secretes an exotoxin that catalyses ADP-ribosylation of an arginine residue on Gsα. This makes the subunit resistant to hydrolysis and the second messenger (in this • case cAMP) remains activated, and this ultimately leads to the fluid and electrolyte loss characteristic of the disease • Pituitary adenomasa • McCune–Albright syndromea • Albright’s hereditary osteodystrophya (or pseudohypoparathyroidism) a See Chapter 4, Endocrinology. 14.2.2 Protein kinases and phosphatases Protein kinases catalyse the transfer of a phosphate group from ATP to a serine, threonine or tyrosine residue on a target protein (the substrate). Phosphorylation of this amino-acid residue results in an alteration in the conformation of the target protein and thus leads to its activation or inactivation. Many growth factor receptors are protein tyrosine kinases (see above). Many of the ‘downstream’ intracellular pathways that are initiated by the activation of a second messenger system involve protein kinases (usually serine kinases in the cytoplasm). In this way an external signal can, through the activation of one receptor, influence a vast array of cellular processes due to a cascade of protein interactions. 14.2.3 Nuclear hormones Not all extracellular signals use second messenger systems to effect changes to the cell. Important exceptions are steroid hormones that bind to an intracellular receptor, allowing the receptor to be freed from its cytosolic membrane-bound anchor (Figure 14.10). The receptor–hormone complex then travels to the nucleus where it binds to specific regions of DNA called hormone-responsive elements (HRE), thereby effecting alterations in the transcription of DNA. Examples of nuclear hormones • • • • Corticosteroids Vitamin D Retinoic acid Sex steroids. 14.2.4 Transcription factors and the regulation of gene expression The human genome is present in two copies in every cell in the body, and is estimated to consist of around 30 000 genes. The spatial and temporal expression of a proportion of these genes (typically 10 000–15 000 genes are expressed in any one cell at any time) determines the differentiation, morphology and functional characteristics of each cell type (the cellular phenotype). Clearly, for cells to maintain a specific identity, this process must be very tightly regulated. Eukaryotic genes consist of exons that are transcribed into the mRNA template, which is translated into protein (Figure 14.11). Exons are separated by introns, which do not code for protein, but have a role in mRNA stability and are spliced out of the pre-mRNA before translation. Sometimes exons are also spliced out to produce variant forms of the protein with tissue-specific functional elements (splice variants). Clearly some genes have a fundamental biological role and will be expressed in all cells at all times (‘housekeeping genes’). However, the transcription of most genes proceeds only when a macromolecular complex (the initiation complex) binds to a region of the 5′ end of genes called the promoter. The assembly of this complex is directed by the presence of transcription factors and facilitates the binding of RNA polymerase, which leads to transcription. Muscle, for example, will contain specific transcription factors that lead to the expression of muscle-specific genes which determine the muscle phenotype. Figure 14.10 The nuclear hormone superfamily of receptors act by controlling gene transcription in the nucleus The promoter A modular arrangement of different elements that act as a binding site for RNA polymerase II and the initiation of transcription The initiation of transcription involves a large complex of multimeric proteins (RNA polymerase • II plus the general transcription factors (GTFs): TFII A–H) • The GTFs can activate transcription of any gene that has a TATA box (see below). • Enhancers Elements that can be at the 5′ or the 3′ end of genes and can vary in distance from the coding sequence itself Enhancers are not obligatory for the initiation of transcription but alter its efficiency in such a • way as to lead to an increase in gene expression. • 5′-Untranslated region The five prime untranslated region (5′-untranslated region or 5′-UTR) is a section of mRNA and the DNA that codes for it. It starts at the transcription start site and ends just before the transcription start codon (usually AUG). The region can contain several regulatory sequences: Figure 14.11 Structure of a typical gene • A ribosome-binding site • Binding sites for proteins that may affect the stability or translation rate of the mRNA • Sequences that promote the initiation of translation. 3′-Untranslated region The three prime untranslated region (3′-UTR), similar to the 5′-UTR, is a section of mRNA and the DNA that codes for it. It starts after the stop codon (usually UAG, UAA or UGA) and may contain several regulatory sequences: A polyadenylation signal: this initiates the cleavage of the transcript, which usually happens • about 30 base pairs downstream. This is then followed by the addition of several hundred adenine residues (poly-A tail) Binding sites for regulatory proteins: these proteins may affect the stability or cellular localisation of the mRNA. AU-rich elements (AREs) are sequences in the 3′-UTR rich in adenine • and uridine nucleotides which can stabilise or destabilise the mRNA depending on the protein bound. Poly-A tail The addition of a stretch of adenine residues (typically 50–200) at the 3′ end of mRNAs protects them from degradation by exonucleases present in the cytoplasm, and aids in transcription termination, export from the nucleus and translation. The length of the adenine repeat may also have an effect on stability; when the tail is shortened the mRNA is enzymatically degraded. Transcription factors Transcription factors are proteins that bind to sequence-specific regions of DNA at the 5′ end of genes called response elements to regulate gene expression. These elements can form part of promoters or enhancers. They can be divided into: Basal transcription factors – involved in the constitutive activation of so-called ‘housekeeping genes’ Inducible transcription factors – involved in the temporal and spatial expression of genes that • underlie tissue phenotype and developmental regulation. • They fall into a number of groups based on their structure: • • • • Helix–loop–helix Helix–turn–helix Zinc finger Leucine zipper. The TATA box is a promoter element that is always located 25–30 base pairs from the start of transcription and serves to anchor RNA polymerase II. Clinical applications of transcription factors An increasing number of diseases are being described where an inherited mutation in • transcription factors leads to a developmental disorder. These are usually complex congenital malformations • Transcription factors can be oncogenes, eg c-myc, TP53 (see section 14.3.2) Many future drugs will be developed to alter gene transcription by acting directly or indirectly • on gene transcription in the manner described above for steroids 14.3 THE MOLECULAR PATHOGENESIS OF CANCER 14.3.1 Somatic evolution of cancer Cancer cells are a clonal population. The accumulation of mutations in multiple genes results in escape from the strictly regulated mechanisms that control the growth and differentiation of somatic cells. It will be evident that some of these genetic ‘errors’ will be inherited and form the basis of a familial tendency to cancer. For cancer to develop, in most cases, an environmentally driven genetic mutation is necessary. Genotoxic damage from ionising radiation and some of the constituents of tobacco smoke fall into this category. In addition, all somatic cell division requires the copying of DNA and this can result in the spontaneous mutations of genes. It is a combination of these three types of genetic mutation (inherited, spontaneous and environmentally determined) that leads to cancer. Therefore, cancer evolution is a complex, multifactorial process. Most tumours show visible abnormalities of chromosome banding on light microscopy, suggesting that as tumours develop they become more bizarre and more prone to genetic error. Although there are some cancer genes that lead to Mendelian (ie monogenic) inheritance of specific tumours, most cancers result from a complex mixture of polygenetic and environmental influences. 14.3.2 Oncogenes Originally identified as genes carried by cancer-causing viruses that are integrated into the host genome and, when expressed, lead to loss of growth control (viral oncogenes are denoted v-onc). They have cellular homologues, proto-oncogenes (denoted c-onc), found in the normal human genome and expressed in normal tissue, that are usually highly conserved in evolution and have central roles in the signal-transduction pathways that control cell growth and differentiation. They can be thought of as exerting a dominant effect in that they cause cancer in the presence of the normal gene product because, in mutating, they have gained a new function. • • • • Ras is a small, monomeric G-protein and is likely to be involved in the transduction of growthpromoting signals. The relative abundance of the active and inactive forms of Ras is controlled by positive and negative regulators of GTP–GDP exchange (GAP and GNRF) (Figure 14.12). Mutations affecting the GTP-binding site prevent GTP hydrolysis and prolong Ras activation. At least a third of sporadic tumours contain acquired somatic mutations in the ras gene Further downstream, after a number of protein kinase steps have been activated, the transduction of growth signals culminates in the activation of the transcription factors Fos and Jun, which in turn induce the transcription of the proto-oncogene myc; this commits the cell to a round of DNA replication and cell division. Mutant forms of these proteins can induce tumour growth The 9:22 balanced translocation (Philadelphia chromosome) found in chronic myeloid leukaemia (CML) generates a composite gene comprising exons from the bcr locus on chromosome 22 and the c-abl locus on chromosome 9, generating a fusion protein with distinct biochemical properties which presumably promote tumour growth In Burkitt’s lymphoma the c-myc gene is transposed from its normal position into the immunoglobulin heavy-chain locus on chromosome 14, resulting in a gross increase in its expression and a potent molecular signal for cells to undergo mitosis (Figure 14.13). 14.3.3 Tumour suppressor genes In contrast to oncogenes these exert a recessive effect, in that both copies must be mutated before tumorigenesis occurs • Mutation results in loss of function These genes normally function to inhibit the cell cycle and therefore, when inactivated, lead to • loss of growth control. • A pivotal role in the cell cycle is played by protein p53, and its gene is the most commonly mutated gene in tumours (breast, colon, etc). It encodes a transcription factor, the normal function of which is to downregulate the cell cycle. Inactivation of p53 is the primary defect in the Li–Fraumeni syndrome (a dominantly inherited monogenic cancer syndrome characterised by breast carcinoma, sarcomas, brain and other tumours), and is a central regulator of apoptosis (see Section 14.4, Apoptosis and disease). Figure 14.12 Activation of the oncoprotein Ras is under reciprocal control by GNRF and GAP Figure 14.13 In chronic myeloid leukaemia the Philadelphia chromosome leads to the production of an oncoprotein 14.4 APOPTOSIS AND DISEASE It has only recently been fully appreciated that widespread cell death occurs in human development and in the normal regulation of cell number in the adult organism. In embryonic development, cells are lost, eg as finger webbing disappears or as neurons are ‘selected’ for survival, by making the appropriate synaptic contact. In postnatal life, the expansion of lymphocyte numbers in response to antigen stimulation must be regulated by the subsequent death of these cells or clonal proliferation would continue unabated. It turns out that this process of naturally occurring cell death is regulated by the activation of a specific set of genes in response to external signals in a process referred to as programmed cell death. The morphological change that accompanies this process is called apoptosis. Cells undergo shrinkage, compaction of chromatin, nuclear and cytoplasmic budding to form membrane-bound apoptotic bodies and finally phagocytosis by surrounding macrophages The activation of intracellular nucleases can be detected by the ‘laddering’ of DNA on • electrophoresis gels, which serves as a marker for apoptosis. • In contrast to necrosis, apoptosis does not induce the release of destructive proteolytic enzymes and free radicals and is thus a non-inflammatory process. Therefore, collateral damage to neighbouring cells is not seen. Most cells seem to rely on a constant supply of survival signals without which they will undergo apoptosis. These are provided by neighbouring cells and the extracellular matrix. The absence or withdrawal of these molecular signals is a trigger to apoptosis. The ‘cell death programme’ is genetically regulated and there are specific proteins that promote or inhibit apoptosis. • • • • A family of proteases called caspases (ICE, or interleukin-1-converting enzyme, is the beststudied example) is central to apoptosis in mammals and is responsible for driving all the structural changes in the nucleus that accompany apoptosis. Caspases have been shown to be present in all cells and thus to prevent apoptosis there must be specific inhibitors of these proteases The Bcl-2 family of molecules inhibit apoptosis by a variety of mechanisms and are thus cytoprotective survival signals. Over-expression of Bcl-2 specifically prevents cells from entering apoptosis and its high expression has been correlated with poor survival from cancer Fas, or CD95, is a transmembrane receptor that belongs to the tumour necrosis factor (TNF) receptor family. The binding of TNF-like ligands to Fas is coupled to the activation of intracellular caspases. Some tumours express the Fas ligand on their surface, thus activating Fas on cytotoxic T lymphocytes, leading to their death (a way of evading immune surveillance) p53 is required for the apoptosis of cells in which DNA has been damaged. The failure of tumour cells to die in the face of genotoxic damage may be due to the accumulation of p53 gene mutations. Programmed cell death can be stimulated by a variety of triggers and leads to the activation of proteases such as ICE that initiate a cascade of morphological changes (collectively known as apoptosis) which result in inevitable phagocytosis. Certain disorders (cancer, autoimmunity and some viral illnesses) are associated with increased • cell survival (and therefore a failure of programmed cell death). Metastatic tumour cells have circumvented the normal environmental cues for survival and can survive in foreign environments Physiological cell death is necessary for the removal of potentially autoreactive T cells during development and for the removal of excess cells after the completion of the immune response. • Animal models of systemic lupus erythematosus (CD95/Fas knockout mice) have implicated apoptosis genes in the pathogenesis of autoimmunity Death by apoptosis can be seen as an evolutionary adaptation to prevent the survival of virally • infected cells. Therefore, viruses have developed strategies for circumventing this. Pox viruses appear to inhibit apoptosis by producing an inhibitor of ICE Excessive cell death due to an excess of signals promoting apoptosis has been hypothesised to • occur in many degenerative disorders where cells have been observed to die by apoptosis. Direct evidence that this actually occurs has yet to be found. Apoptosis may be initiated by two main mechanisms termed the ‘intrinsic’ and ‘extrinsic pathways’. In the intrinsic pathway the cell makes its own decision that the cell is no longer viable and that it should undergo apoptosis. It does this in response to internal damage due to such things as reactive oxygen species, DNA or mitochondrial damage. The damage caused is determined to be significant enough that the cell is no longer viable or if allowed to live would become tumorigenic. The pathway can be seen in Figure 14.14 in which the caspase cascade is activated by a complex of caspase 9 in combination with cytochrome c and Apaf-1. The extrinsic pathway is when an external stimulus leads to the activation of transmembrane death receptors, resulting in a healthy cell committing suicide. The death receptors are members of the TNF-receptor gene superfamily and the main ligands are FasL, TNF-α, Apo3L and Apo2L. The extrinsic pathway is used in tissue remodelling, limiting the clonal expansion of immune cells and maintaining tissue homeostasis by maintain equilibrium between cell proliferation and cell death. The main differences between the intrinsic and extrinsic pathways are that the extrinsic pathway is not mitochrondrially mediated, but rather activated by a death receptor, and that the upstream caspases in the caspase cascade are caspases 8 or 10 in the extrinsic pathway rather than caspase 9 in the intrinsic pathway (Figure 14.15). Figure 14.14 Apoptosis, the intrinsic pathway 14.5 MOLECULAR REGULATION OF VASCULAR TONE Both the regulation of systemic arterial blood pressure and the local control of the microcirculation in organs such as the kidney and the brain are vital for the maintenance of homeostasis. In recent years there has been an explosion

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